TWI331143B - Benzothiadiazepine derivatives, process for preparing them, and pharmaceutical composition comprising them - Google Patents

Abstract

The present invention relates to compounds of formula (I) wherein R<SUP>v</SUP>, R<SUP>1</SUP>, R<SUP>2</SUP>, R<SUP>x</SUP>, R<SUP>y</SUP>, M, R<SUP>z</SUP>, v, R<SUP>3</SUP>, R<SUP>4</SUP>, R<SUP>5 </SUP>and R<SUP>6 </SUP>are as defined within; pharmaceutically acceptable salts, solvates, solvates of such salts and prodrugs thereof and their use as ileal bile acid transport (IBAT) inhibitors for the treatment of hyperlipidaemia. Processes for their manufacture and pharmaceutical compositions containing them are also described.

Description

1331143 A7 B7 V. INSTRUCTIONS (2) Alcoholemia (see, for example, "Bismic acid and cholesterol interact with non-systemic agents with low blood cholesterol properties" 'Biochemica et Biophysica Acta, 1210 (1994) 255-2 87) . Therefore, a suitable compound having such an activity of inhibiting IB AT can also be used for the treatment of a hyperlipidemia condition. Compounds having such IBAT inhibitory activity have been described, for example, WO 93/16055, WO 94/18183, WO 94/18184 'WO 96/05188 'WO 96/08484 'WO 96/16051 'WO 97/33882 ' WO 98/ 38182 'WO 99/35135 'WO 98/40375 'WO 99/35 1 53 , WO 99/64409, WO 99/64410, WO 00/01687, WO 00/47568, WO 00/61568, WO 01/68906, DE Compounds as described in WO 00/38728, WO 00/38729, WO 01/68906 and EP 0 864 582. WO 00/38725, WO 00/38727, WO 00/38727. The invention further relates to the use of the compound of the invention for the treatment of disorders and disorders of lipodystrophy such as hyperlipidemia, hypertriglyceridemia, hyperalbuminemia (high LDL), very high/5 lipoprotein blood Use (high VLDL), hyperlactinemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia, and low alpha lipoproteinemia (low HDL). In addition, these compounds are expected to be useful in the prevention and treatment of different clinical conditions such as atherosclerosis 'arteriosclerosis, rhythm irregularities, high thrombotic conditions, vascular dysfunction, endothelial dysfunction, cardiac disorders, coronary heart disease, cardiovascular disease, myocardial Infarction, angina pectoris, peripheral vascular disease, cardiovascular vascular tissue such as heart inflammation, petal touch, vascular distribution, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fat marks, white blood cells, single cells and/or macrophages Infiltration, thickening of intravascular fistula, thinning of the middle layer of the artery, infection and surgical trauma and vascular embolism, wind and transient hematopoietic shock. -;--_~5 ~ This paper size is applicable to China National Standard (CNS) Α4 specifications (21〇Χ297 mm) Α7

The present invention is based on the discovery that certain benzothiazepine compounds unexpectedly inhibit hydrazine. This property is expected to have value for the treatment of disease states associated with hyperlipidemia conditions. Accordingly, the present invention provides a compound of formula (I):

(Rz)v (I) where:

Rv is selected from hydrogen or CU6 alkyl; one of R1 and R2 is selected from hydrogen, Ci 6 alkyl or C2 6 alkenyl and the other is selected from Cw alkyl or t2-6;

Rx and Ry are independently selected from the group consisting of hydrogen, hydroxy, amine, arsenyl, Cl.6 alkyl, Cw alkoxy, alkyl)amine, hydrazine, fluorene-((ν6 alkyl) 2 amine, ^.6

院0基s(cj M f. at I alk 2_yl S(0)a wherein a is 〇 to 2; from -N- or -CH-; from halo, nitro, cyano, hydroxy, amine Carboxy, aminomethylmercapto, thiol'amine sulfonyl, Cw alkyl, 'C2.6 alkenyl, C2.6 alkynyl, Cw alkoxy' CN6 alkyl fluorenyl, Cw alkanoyloxy Alkyl, NdCw alkyl), amine, Ν-πΜalkyl) 2 amine, Cw alkyl amide, ivKCw alkyl) amide, hydrazine, Ν-ίί: &quot;alkyl 2 Aminomethyl thiol, Cw alkyl-6 - ^ paper scale applicable to China National Standard (CNS) A4 specification (210 X 297 mm) V. Invention description (4) s (〇) a where a is 0 to 2. CN6 alkoxycarbonyl, N-(CU6 alkyl)amine sulfonyl and N,N-(C|.6)ylamine 2 hydrazine; v is 〇-5; one of R4 and R5 is The basis of formula (IA):

R3 and R6 and the other R4 and R5 are independently selected from the group consisting of hydrogen, dentate, nitro, cyano, hydroxy, amine, carboxy, aminomethylguanidino, thiol, sulfonyl, CU4 alkyl, C2.4 alkenyl, c2_4 alkynyl, Cm alkoxy, Cm alkyl fluorenyl, Cw alkyl decyloxy, NJCw alkyl) amine, hydrazine, Ν-β decyl) 2 amine, Cw alkyl fluorenyl Amino, N-(Cn4 alkyl)aminomercapto, fluorene, fluorenyl-(CU4 alkyl) 2 amino fluorenyl, Cm alkyl S(0)a wherein a is 〇 to 2, Cw alkoxy Alkylcarbonyl, N-(Ci_4 alkyl)amine sulfonyl and alkyl) 2 amine sulfonyl; wherein R3 and R6 and the other R4 and R5 may be substituted on the carbon by one or more R16; X is - 0-, -N(Ra)-, -S(0)b- or -CH(Ra)-; wherein Ra is argon.. or Cu6 alkyl and b is 0-2; .':i ring A is aromatic Or a heteroaryl group; wherein ring A is optionally substituted with one or more substituents selected from Ri7; r7 is hydrogen, Cm alkyl, carbocyclyl or heterocyclyl; wherein R7 is optionally selected by one or more Substituted from a substituent of R18; R8 is hydrogen or C,-4 alkyl;

V. Description of the invention (5) R9 is hydrogen or C^.4 pit; R is hydrogen, C, .4 alkyl, carbocyclyl or heterocyclic; wherein Rio is optionally selected from or substituted for R1 9 Replacement of substituents; -P(0)(0Rc)(ORd)-, R11 is drum base, exact group, hexylene group, phosphine base _P(0)(0H)(0Rc), -P(〇) (OH)(Rd) or wherein RC&amp;Rd is independently selected from the group consisting of Cl.6 alkyl; or the base of formula (IB) or (IC)

, -〇- and -S(0)a-; wherein a is 〇_2, v is 1-2' Rs and Rt are independently selected from hydrogen or, as the case may be, a Cm alkyl group substituted by a R26 group and Rn is hydrogen or Cl4 alkyl; R12 is hydrogen or CK4 alkyl; R13 and Ri4 are independently selected from hydrogen, Cl-6 alkyl, carbocyclic or heterocyclic; and when q is hydrazine, RM may in turn be selected from hydroxy; And R丨4 may be independently substituted with one or more substituents selected from R20; R is an enradyl, a contiguous group, a hexylene group, a phosphine, a ρ(〇)(1), a _P(〇)(OH) (ORe) ' _P(0)(0H)(Re) or -P(0)(0Re)(Rf) wherein RiRf is independently selected from C _6 alkyl; P is 1-3; wherein the value of R13 is Same or different; q is 0-1; r is 0-3; where R14 values can be the same or different; this paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1331143 A7 B7

5. Description of the invention (m is 〇-2; wherein the values of R10 may be the same or different, η is 1-3; wherein the value of R7 may be the same or different; the ring enthalpy is substituted on carbon by a group selected from R23 a nitrogen-bonded heterocyclic group 'and optionally substituted with one or more R groups on the carbon, and wherein if the gas-bonded heterocyclic group contains a -ΝΗ- group, the nitrogen may optionally be selected from R25 Substituent; R16, R17 and R18 are independently selected from the group consisting of a dentate group, a nitro group, a cyano group, a hydroxyl group, an amino group 'carboxy group, an amino fluorenyl' thiol group, an amine sulfonyl group, a Cm alkyl group, and a fluorene 2- 4 dilute base, 〇2.4 fast base, (^1_4 oxooxy, 〇1.4 醯 匚, 匚1.4 calcyloxy, alkyl) amine, N, N-(Ci-4) 2 amine , CU4, alkylamino, N-Cq.4 alkyl)aminoindenyl, N,N-(Cu4 alkyl)2aminocarboxamyl, Cw alkyl S(0)a wherein a is 0 To 2, Cw alkoxycarbonyl, N_(Cm alkyl)amine sulfonyl and hydrazine, Ν-ίΟ..4 alkyl) 2 amine sulfonyl; wherein R16, R17 and R18 can be independently on carbon Substituted by one or more R21; R19, R20, R24 and r26 are independently selected from halo, nitro 'cyano, hydroxy, amine, carboxy , aminomethanyl, thiol, sulfonyl, Cw alkyl, C2-4 dilute, C2.4 fast radical, Ci_4 炫•oxy, C 1 _4 calcinyl, C 1 4 Alkoxy, N-(C-4-alkyl)amino, fluorene, Ν-β decyl) 2 amine, (^. 4 alkylalkylamino, NJCw alkyl) aminomethyl fluorenyl, hydrazine , Ν-^μalkyl) 2 amino fluorenyl, Cw alkyl S(0)a wherein a is hydrazine to 2, Cw alkoxycarbonyl, NVCm alkyl) aminoxime, alkyl) 2 amine Sulfonyl, carbocyclyl, heterocyclyl, benzyloxycarbonylamino, (CU4 alkyl) 3 decyl, sulfo, hydrazino, fluorenyl, phosphinyl, -P(〇)(〇Ra) (〇Rb), -P(〇)(〇H)(ORa), -P(0)(0H)(Ra) or -P(0)(0Ra)(Rb), wherein Ra and Rb are independently selected from ** 9 - This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

Binding

Line V 1331143 A7 B7 彡, invention description (7) C1-6 alkyl; wherein R19, R2G, R24 and R26 may be independently substituted on the carbon by one or more R22; R21 and R22 are independently selected from halo , hydroxy, cyano, aminomethyl decyl, ureido, amine, acetyl, sulfhydryl, thiol, amine, trifluoromethyl, di i methoxy, methyl, ethyl, Methoxy, ethoxy, ethylene, propyl, ethynyl, decyloxy, decyl, ethyl hydrazino, decylamino, ethoxylated, ethoxylated, fluorene Amine, diammonium, N-methylaminoindenyl, N,N-didecylaminoindenyl, sulfonylthio, methylsulfinyl, decanesulfonyl, N- Hydrazinylsulfonyl and N,N-didecylamine sulfonyl; R23 is carboxyl, sulfo, sulfinyl, phosphonium, -P(〇)(〇Rg)(〇Rh), -P (0) (0H) (0Rg), -P(〇)(〇H)(RS) or -P(〇)(〇Rg)(Rh) wherein Rg and Rh are independently selected from Cw alkyl; R25 is selected From Ci-6 alkyl, (^_6 alkyl fluorenyl, CN6 alkylsulfonyl, Cm alkoxycarbonyl, amino fluorenyl, alkyl) amino fluorenyl, N, N-(C!· 6 alkyl) 2 amine group Acyl 'groups Qian, Qian oxycarbonyl group, acyl and Yue stupid stupid continued brewing group; or a pharmaceutically acceptable salt, solvate, solvate of such salts or prodrugs thereof. According to still another feature of the invention, there is provided a compound of formula (I): • 10 - the paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 public) A7 B7 V. Description of invention (8

among them:

R R is selected from hydrogen or Cl 6 alkyl; one of R 1 and R 2 is selected from hydrogen or Cl 6 alkyl and the other is selected from C -6 alkyl; R &amp; Ry is independently selected from hydrogen, thiol, amine Base, argon-sulfuryl, Ci.6 alkyl, Cu alkoxy, alkyl)amine, hydrazine, Ν-βΜalkyl) 2 amine 'C,-6 alkyl S(0)a where a is 〇 to 2; Μ is selected from -N- or -CH-;

Rz is selected from the group consisting of a halogen group, a nitro group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an aminomethyl fluorenyl group, a thiol group, an amine sulfonyl group, a Cu6 alkyl group, a C2.6 alkenyl group, and a <2- 6 alkynyl, (^.6 alkylalkyl, Cw alkyl sulfoxy, ISKCw alkyl) amine, hydrazine, fluorenyl-(Cw alkyl) 2 amine, d. 6 alkyl fluorenyl, alkyl Aminomethyl hydrazino, hydrazine, hydrazine-^alkyl group) 2 aminomethyl fluorenyl, Cu alkyl S(0)a wherein a is 0 to 2, Ci. 6 alkoxycarbonyl, NJCu alkyl) Aminesulfonyl and hydrazine, Ν-β decyl) 2 amine sulfonyl; v is 0 - 5, one of R 4 and R 5 is a group of formula (ΙΑ): .......:; -11 - This paper scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm) mm3. A7 B7 V. Description of invention (9)

R3 and R6 and the other R4 and R5 are independently selected from the group consisting of argon, a functional group, a nitro group, a cyanide group, a hydroxyl group, an amine group, a carboxyl group, an amino group, a hydrogen group, a sulfonium group, and an amine sulfonate. Base, Cu alkyl, C2.4 alkenyl, C2.4 alkynyl, C, 4 alkoxy, Cm alkyl fluorenyl, Cm alkyl fluorenyloxy, alkyl) amine, hydrazine, Ν-β decyl 2) an amine group, a C m alkylalkylamino group, an N-(Cm alkyl)aminocarbamyl group, an anthracene, a fluorenyl-(Cm alkyl) 2 amine fluorenyl group, a Cw alkyl group S(0)a a is 0 to 2, Cw alkoxycarbonyl, N-(Ci_4 alkyl)aminesulfonyl and NW-CC^alkyl)2aminesulfonyl; wherein R3 and R6 and another R4 and R5 may be Substituting one or more R16 on carbon; X is -0-, -N(Ra)-, -S(0)b- or -CH(Ra)·; wherein Ra is hydrogen or Cu alkyl and b is 0 -2 ; Ring A is aryl or heteroaryl; wherein ring A is optionally substituted with one or more substituents selected from R17; R7 is hydrogen, CN4 alkyl, carbocyclyl or heterocyclyl; The case is substituted by one or more substituents selected from R18; R8 is argon or CN4 alkyl; R9 is hydrogen or Cm alkyl; R1Q is argon, Cm alkyl, carbocyclyl or heterocyclic; wherein R1Q is optionally One or more Substituent substitution from R19; -12- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) T33ll2f3*~_ A7 B7 V. Description of invention (10) R11 is carboxyl group, sulfo group, Sulfosyl, phosphinium, -p(〇)(〇Re:K〇Rd), -P(0)(0H)(0Rc), -P(0)(0H)(Rd) or -P(〇 (〇Rc)(Rd) wherein rc and the system are independently selected from (: 丨.6 alkyl; or 尺1丨 (IB):

(IB) where: Y is -N(Rn)·, -N(Rn)C(0)-, -0-, and -S(0)a-; wherein a is 〇_2 and Rn is hydrogen or Cw R12 is hydrogen or CN4 alkyl; R13 and R14 are independently selected from hydrogen, Cw alkyl, carbocyclyl or heterocyclyl; wherein R13 and R14 are independently substituted by one or more substituents selected from R2Q, as appropriate ; R is a rebel, a contiguous, a subcontinuation, a squaring, -P(〇)(OH)(ORe), -P(0)(0H)(Re), or -P(0)(0Re) (Rf) wherein R^Rf is independently selected from (: 丨.6 alkyl; p is 1-3; wherein R13 may be the same or different; q is 0-1, r is 0-3; wherein R14 is m may be the same or different; m is 0-2; wherein the values of RIG may be the same or different; η is 1-3; wherein the values of R7 may be the same or different; · R16, R17 and R18 are independently selected from the group consisting of a dentate group and a nitro group. 'Cyano group, thiol group, amine group, thiol group, amine aryl group, thiol group, fluorenyl group, C14 alkyl group, C2-4 alkenyl group, C2_4 alkynyl group, Ci.4 alkoxy group, CU4 Alkyl fluorenyl, c14 succinic acid-13- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1331143 A7 __B7 _ V. Description of invention (11) Oxygen, N-CCw alkyl) Amine, NA-CCm alkyl) 2 Base, c, .4 alkylalkylamino, N-(CN4 alkyl)amino fluorenyl, alkyl) 2 amino fluorenyl, Ci. 4 alkyl S(0)a wherein a is hydrazine to 2, Cw alkoxycarbonyl, Ν-(C丨.4 alkyl)amine sulfonyl and alkyl) 2 amine sulfonyl: wherein R16, R17 and R18 may independently pass one or more carbons as appropriate R21 substituted; R19 and R2Q are independently selected from the group consisting of a nitro group, a nitro group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an amino fluorenyl group, a thiol group, an amine sulfonyl group, a CN4 alkyl group, a C2.4 alkenyl group. , C2-4 alkynyl group, Cm alkoxy group, Cw decyl group, Cw-branched oxy group, N-CCm alkyl group), hydrazine, Ν-^μalkyl) 2 amine group, cN4 alkyl fluorenyl group Amino, N-(Ci-4 alkyl)aminoindenyl, n,n-(cN4 alkyl)2aminocarboxamidine, Cm alkyl S(0)a wherein a is 0 to 2, Ci -4 alkoxycarbonyl, NJCm alkyl)amine, anthracene, Ν-ίί^·4 alkyl) 2 amine fluorenyl, carbocyclyl, heterocyclyl, contiguous, hexylene, fluorenyl 'phosphinium, -P(〇)(〇Ra)(〇Rb), -P(0)(0H)(0Ra), -P(0)(0H)(Ra) or -P(〇)(〇 Ra) (Rb), wherein ... and Rb are independently selected from Cm alkyl; wherein R19 and R2Q can be independently broken or Multiple R22 substituted; R21 and R22 are independently selected from halo, hydroxy, cyano, carbamoyl, sulfhydryl, amine, deterministic, thiol, thiol 'amine hydrazino, tris- fluorenyl , trifluoromethoxy, methyl, ethyl, methoxy, ethoxy 'vinyl, allyl, ethynyl 'methoxycarbonyl, fluorenyl, ethenyl, alanyl, B Amidino, ethoxylated, methylamino, dimethylamino, N-methylaminocarbamimidyl, N,N-dimethylaminocarbamimidyl, methylthio, fluorenyl , A-burning base, N-methylamine continuation base and N,N-dimethylamine are the base; -14- This paper scale is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) A7 V. Description of the invention (B7 12) or its medicinal remedies. To be a salt, a solvate, a solvate of this salt or its precursor. According to another aspect of the invention, there is provided a compound of formula (I):

R is selected from hydrogen or (^-6 alkyl; one of I 2 R and R is selected from hydrogen or Ci6 alkyl and the other is selected from Ci 6 alkyl;

Rx and Ry are independently selected from the group consisting of hydrogen, hydroxy, amine, arsenyl, Cw alkyl, CN6, oxy, N-(Cl.6 alkyl)amine, n,N-(CN6 alkyl)2 amine , cN6 炫基 S(0) a wherein a is 〇 to 2; , lanthanide is selected from -N- or -CH-;

Rz is selected from the group consisting of a halogen group, a nitro group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an aminomercapto group, a thiol group, an amine aryl group, a Ct.6 alkyl group, a c2_6 alkenyl group, and a C2.6 alkynyl group. , Cu Institute gas base, 〇: 1.6 dazzling base, C|-6 醢 醢 methoxy, NJCu 炫) amine, N, N-(Cb6 alkyl) 2 amine, Cu alkyl fluorenyl amine ' NdCw alkyl)aminoindenyl, alkyl)2aminoindenyl, CN6alkyl S(0)a wherein a is 0 to 2, Cw alkoxycarbonyl, NqCu alkyl)amine sulfonate-15 - The paper size is applicable to the Chinese National Standard (CNS) A4 specification (210X 297 mm) A7

And alkyl) 2 amine sulfonyl; v is 〇-5; one of R4 and R5 is a group of formula (IA):

(IA) R3 and R6 and the other R4 and R5 are independently selected from the group consisting of hydrogen, a functional group, a nitro 'cyano group, a hydroxyl group, an amine group, a carboxyl group, an amino fluorenyl group, a thiol group, an amine sulfonyl group, and a Ct group. -4 alkyl, C2-4 alkenyl, c2.4 alkynyl, Cm alkoxy, Cw alkanoyl, C!·4 alkylalkyloxy, alkyl)amine, hydrazine, hydrazine Amino, Cm alkyl fluorenyl, N-(CU4 alkyl)amino fluorenyl, hydrazine, fluorenyl-(CU4 alkyl) 2 aminomethyl fluorenyl, Cl. 4 alkyl s (〇 Where a is 〇 to 2, Cm alkoxycarbonyl, alkyl)amine sulfonyl and alkyl) 2 amine sulfonate; wherein R3 and R6 and the other R4 and R5 may optionally be on the carbon or Substituting a plurality of R16; X is -〇-, -N(Ra)-, -S(0)b- or -CH(Ra)-; wherein Ra is &amp; heptyl and b is 0-2; fly 2 Ci -6 Ring A is substituted with a substituent of an aryl or heteroaryl group; wherein ring A is optionally one or more selected from the group consisting of Rl7 R7 is hydrogen, Cm alkyl, carbocyclic or heterocyclic; Substituting a plurality of substituents selected from R18; month R8 is hydrogen or Cm alkyl; R9 is nitrogen or Ci. 4 yard; _ -16-

This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 mm) 1331143

R10 is argon, Ci_4 alkyl, carbocyclyl or heterocyclic; wherein Rio is optionally substituted with one or more substituents selected from R19; R11 is carboxy, sulfo, sulfinyl, phosphonium, _p ( 〇y(GR'c)(〇Rd), _p(〇)(OH)(ORc), -P(〇)(〇H)(Rd) or wherein RiRd is independently selected from CBu 6 alkyl; or R11 The basis of the formula (IB) or (IC):

Y is -N(Rn)-, -N(Rn)C(0)-, -Ν(ΙΙη)(:(0)(€ί15Κ/)νΝ(ΙΙη)(:(0)_, -〇- and -S(0)a-; wherein a is 0-2, ν is 1-2, Rs&amp;Rt is independently selected from hydrogen or optionally substituted by the R26 group iCw alkyl and Rn is hydrogen or Cw alkyl; R12 is Hydrogen or Cm alkyl; R13 and R14 are independently selected from hydrogen, Cw alkyl, carbocyclyl or heterocyclic; and when q is hydrazine, R14 may in turn be selected from hydroxy; wherein Rn&amp;Ru may be independently Or a plurality of substituents selected from R20; R15 is carboxyl, sulfo, sulfinyl, phosphonium, _p(〇)(〇Re)(〇Rf), -P(〇)(OH)(ORe) , -P(〇)(〇H)(Re) or -P(0)(0Re)(Rf) wherein R%Rf is independently selected from Cw alkyl; 八p is 1-3; wherein the value of R13 is the same Or different; q is 0-1 r is 〇-3; wherein the value of R14 can be the same or different; m is 〇·2; wherein the value of Rie can be the same or different; _ -17- This paper scale is applicable to the national standard of China (CNS) A4 size (210X 297 mm)

Binding

I 1331143 A7 _ B7 V. DESCRIPTION OF THE INVENTION (15) η is 1·3; wherein the value of R7 may be the same or different; the cyclic oxime is a heterocyclic group bonded to a nitrogen bond on the carbon via a group selected from R23. And optionally substituted with one or more R24 groups on the carbon; and wherein if the nitrogen-bonded heterocyclic group contains a -ΝΗ- group, the nitrogen may optionally be substituted with a group selected from R25; R16, R17 and R18 Is independently selected from the group consisting of a dentate group, a nitro group, a cyano group, a hydroxyl group, an amine group, a carboxyl group, an aminomethyl sulfonyl group, a thiol group, an amine sulfonyl 'Cw alkyl group, a C2-4 alkenyl group, a C2.4 alkynyl group. , Ci.4 alkoxy, CN4 alkyl fluorenyl, Cw alkyl decyloxy, NqCw alkyl) amine, NW-CCw alkyl) 2 amine, CN4 alkyl fluorenyl, alkyl) amine hydrazine Mercapto, alkyl) 2 amino fluorenyl, CN4 alkyl S(0)a wherein a is 0 to 2, Cw alkoxycarbonyl, fluorene-(C1.4 alkyl)amine, and N, N-(Ci-4 alkyl) 2 amine continuation; wherein R16, R17 and R18 may be independently substituted on the carbon by one or more R21; R19, R20, R24 and R26 are independently selected from halo, Nitro, cyano, hydroxy, amine, carboxyl, amino fluorenyl, thiol, sulfonyl, Cw Alkyl, 匚2-4 dilute, 匚2.4 fast radical, 匚1.4 alkoxy, (^1.4Hyun*, 〇1_4 炫&gt; mercaptooxy, N-(C|.4 alkyl)amine Base, oxime, Ν-^μalkyl) 2 amine group, (^.4 decylamino group, alkyl) aminocarbamyl group, n,N-(Cm alkyl)2 amine broth base, (!) 1-4 burnt base 8 (0) £1 where &amp; is 〇 to 2, (^1.4 methoxyl group, alkyl) sulfonamide, hydrazine, Ν-^μalkyl) 2 amine Sulfonyl, carbocyclyl, heterocyclyl, oxime carbonylamino, contiguous, arginyl, ruthenium, phosphine, -P(0)(0Ra)(0Rb), -P(0)( 0H) (0Ra), _p(〇)(〇H)(Ra) or -P(0)(0Ra)(Rb) ' wherein Ra and Rb are independently selected from Cl.6 alkyl; wherein R19, R2G, R24 And R26 can be taken independently on the carbon by one or more R22 -18- This paper scale applies Chinese National Standard (CNS) A4 specification (210 X 297 public attack -- 丄331143 A7 B7 V. Invention description (π ) R21 and R22 are independently selected from halo, hydroxy, cyano, amide, ureido, amine, nitro, carboxy, thiol, sulfonyl, trifluoromethyl, difluoro Alkoxy, methyl, ethyl, decyloxy, ethoxy, vinyl , allyl, ethynyl, methoxycarbonyl, decyl, ethenyl, decylamino, etidinyl, ethoxylated, decylamino, dimethylamino, N-decylamine Based on ugly base, N,N-dimethylamino fluorenyl, methylthio, methylsulfinyl, methanesulfonyl, N-decylamine sulfonyl and N,N-dimethyl Aminesulfonyl; R23 is a carboxyl group, a sulfo group, a sulfinyl group, a phosphonium group, _P(0)(0Rg)(0Rh), -p(〇)(OH)(ORg), .? (0) (0in (118) or _1&gt;(0)(01^)^11) wherein 1^ and 1^ are independently selected from CN6 alkyl; R25 is selected from (^-6 alkyl, Cw alkane) Sulfhydryl, Cu alkylsulfonyl, C!.6 alkoxy, amidino, N_(Cl-6 alkyl)aminoindenyl, N,n-(Cw alkyl)2 Aminomethylmercapto, fluorenyl, fluorenyloxy, benzhydryl, and phenylsulfonyl; or a pharmaceutically acceptable salt, solvate, solvate or prodrug thereof. / In the present specification, The alkyl group, the term includes both straight-chain and branched-chain alkyl groups, but with respect to individual alkyl groups such as ''propyl group, only specifically means straight-chain. For example, "Cl 6 alkyl group" includes 〇^-4 alkyl group. , Cl_3 alkyl, propyl, isopropyl and tert-butyl. However, the individual stimuli such as "propyl" are only particularly indicated by direct bonds and related to individual branched alkyl groups such as "isopropyl" are only particularly representative of branches. Chain. Similar transformations can be applied to other groups such as "phenyl Cl," can contain stupid Cl to form, word -19-1331143

Base, 1-phenylethyl and 2-phenylethyl. "dentate," _ word for fluorine, gas, '/ odor and hydrazine. When the substituent is optionally selected from "one or more,", it is understood that this definition encompasses all substituents selected from a particular group or A substituent selected from two or more specific groups. "Heteroaryl" is a fully unsaturated, mono or bicyclic ring containing from 3 to 12 atoms, at least one of which is selected from nitrogen, sulfur or oxygen, and may be bonded via carbon or nitrogen unless otherwise stated. More preferably, "heteroaryl, which represents a fully unsaturated monocyclic ring containing 5 or 6 atoms or a bicyclic ring containing 9 or 10 atoms", at least one of which is selected from nitrogen, sulfur or oxygen, unless otherwise stated It may be bonded via carbon or nitrogen. "Heteroaryl, examples and suitable values are phenyl, isoxazolyl, imidazolyl, indolyl, pyrimidine, iso-P-decyl, tri. All base, taste α Nanji, astringent base, mouth bite base, leaf cultivating base, tower tillage base, Ρ 咬 base and Β 淋 基 base. Preferably, "heteroaryl," the term stands for phenyl or fluorenyl. "Aryl" is a fully unsaturated, mono or bicyclic ring containing from 3 to 12 atoms. Preferably "aryl" represents 5 or 6 A single ring of one atom or a double ring containing 9 or 1 atom. The appropriate value of "aryl" is a stupid or a fluorenyl group. In particular, "aryl" is a stupid group. "Heterocyclyl" is a saturated, partially saturated or unsaturated, mono or bicyclic ring containing from 3 to 12 atoms, at least one of which is selected from nitrogen, sulfur or oxygen, unless otherwise stated 'which may be bonded via carbon or nitrogen Wherein the -CH2- group may be optionally oxidized by a -C(0)-yl substitution or a cyclic sulfur atom to form an S-oxide. Preferably, "heterocyclyl" represents a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 5 or 6 atoms, at least one of which is selected from nitrogen, sulfur or oxygen, unless otherwise stated, which may be via carbon or Nitrogen bonding, where -CHr group can be replaced by -C(0)-based __ -20- This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 public) 1331143 V. Description of invention (π or ring sulfur atom can be phased, lowered ^. oxidized to form s-oxide. "Heterocyclic λ", the appropriate value is oxazolidine * 基 base case and 2,5_ two gas generation. ; base, inhibiting base, 2-... base, (d), 24: base: 2_stupylTM, 1 small dioxo tetrakis), 2-oxazolinone, monooxazoline ,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Base, 2 b benzophenone. Nanji, Xiaoqiu Φ, J·-gas °% base, tetrahydropyranyl 'piperidinyl, 丨_oxygen, a milky saponin m, thiopental, U·-based, tetrahydrogen咗 咗 A 1 〇 乳 乳 代 代 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 、 : : : : : : : : : : : : : : : Its &quot;Kisezosazolyl, isothiazolyl, ,,-sodium-l,M-triazolyl, piperidinyl, oxazolidine, pyridin, "Oggan &amp; And a different "base well base" than a bite base ... than (four) base, 'linker 2 bond ^ heterocyclyl, which is 3] 2 atoms, at least one of which is nitrogen saturated or unsaturated, single or Wei, and (iv) the ring system is bonded to the group of formula (IC) via this nitrogen atom, and the ruthenium may contain other heteroatoms selected from nitrogen, melon or oxygen, wherein the _Ch2_ group may be replaced by (9) The ring sulfur atom may be oxidized to form an s_oxide. Preferably, the "gas-bonded heterocyclic group" is a saturated, partially saturated or unsaturated monocyclic or bicyclic ring containing 5 or 6 atoms, at least one of which is nitrogen. The heterocyclic ring is bonded to the carbonyl of formula (1C) via this I shoulder. Further, it may contain other heteroatoms selected from nitrogen, sulfur or oxygen, wherein the -CH2. group may be optionally oxidized by the _c(〇)· group or the cyclic sulfur atom may be oxidized to form an S-oxide. Heterocyclic groups, examples and appropriate values are - 21 - ^ Paper size suitable for SS household materials (CNS) A4 specifications (21GX 297 mm) ------ -------- 1331143

Alkyl group, pyrrolidinyl group, oxazole, oxime group, pyrazole biting group, piperidinyl group and guanidin-1-yl group. In particular, a "nitrogen-bonded heterocyclic group, which is pyrrolidin-buyl. /Carbocyclic oxime" is a saturated, partially saturated or unsaturated 'early or double carbon ring' containing 3·12 atoms. _CH2_ The base can be replaced by the _c(〇) base. Preferably, the "carbocyclic group" is a single ring of 5 or 6 atoms or a double ring of 9 or 1 atom. Suitable values for the anodic ring include cyclopropyl, cyclobutyl, 1-oxocyclopentyl 'cyclopentyl, % pentenyl, it hexyl' cyclohexenyl, phenyl, decyl, tetrahydronaphthyl , printed base or 1_oxoindan. Especially "carbocyclyl," is cyclopropyl, butylbutyl, 1-oxocyclopentyl, cyclopentyl, cyclopentenyl'cyclohexyl'cyclohexenyl, phenyl or 1-oxoindole Fully based. "C!-6 alkanoyloxy" and "C!.4 alkylalkyloxy," examples being ethoxycarbonyl. Examples of the "Cw alkyl carbonyl group" and the "Ci-4 alkyl fluorenylcarbonyl group" include a decyloxycarbonyl group, an ethoxycarbonyl group, a n- and a tert-butoxycarbonyl group. Examples of the "c"-6 alkoxy group, and the "Cm alkoxy group" include a decyloxy group, an ethoxy group, and a propoxy group. Examples of the "ci6 alkyl fluorenylamino group" and the "Cm alkyl fluorenyl amine group" include hydrazine. Examples of guanylamino 'acetamidoamine and propylamine" "Cu alkyl S(0)a wherein 3 is 〇 to 2" and "Cu alkyl S(0) a wherein a is 0 to 2" Methylthio, ethylthio, fluorenyl hydrazide, ethyl sulphate, hydrazine sulfonyl and ethyl thiol. "ci6 醯 ' ' and C! · 4 醯 醯 base '' Examples include propylene and ethyl thiol. "n_(c16 炫)amino" and "N^Ci.4 leu" amine, 'examples include methylamino and ethylamine. "NWw·pile-based h-amino" and "N,N-( The CU4 alkyl)2 amine group, examples include a bis-N-nonylamino group, a bis-(N-ethyl)amino group, and an N-ethyl fluorene-fluorenylamino group. Examples of "C2.6 alkenyl" and "C:2.4 alkenyl" are vinyl, allyl and propenyl. Examples of "CM alkynyl" and "CM alkynyl" are ethynyl, 丨-propynyl and _-22- This paper scale applies to Chinese National Standard (CMS) A4 specification (210X 297 mm) 1331143 A7 B7 V. DESCRIPTION OF THE INVENTION (a) vinegar, C μ calcined benzyloxymethyl ester such as trimethyl ethoxymethyl methyl ester, brewing δ, CM cycloalkoxycarbonyloxy C 6 alkyl ester such as hydrazine _cyclohexylcarbonyloxyethyl vinegar; I,3-dioxol-2-ketomethyl ester such as 5-methyl·1,3-dioxol-2-one fluorenyl An ester; and an alkoxycarbonyloxyethyl aceton such as 1-methoxycarbonyloxyethyl ester and which can be formed on any of the carboxyl groups in the compounds of the invention. The in vivo hydrolysable ester of the compound of formula (I) containing a thiol group comprises an inorganic ester such as phosphoric acid S and an α-decyloxyalkyl ester and a related compound which produces an original hydroxyl group as a result of in vivo hydrolysis cleavage of the ester. Examples of the α-methoxyalkyl esters include an ethoxycarbonyloxy group and a 2,2-dimercaptopropoxycarbonyl group. The choice of the hydrolyzable ester of the hydroxyl group includes an alkane group, a claudyl group, a benzylidene group, a substituted benzoyl group, a phenylethenyl group, an alkoxycarbonyl group (obtaining an alkyl carbonate). , a dialkylamino aryl group and a fluorenyl-(dialkylaminoethyl)- fluorenylalkylaminomethyl hydrazino group (obtaining an amino decanoate), a dialkylaminoethyl fluorenyl group and a carboxy acetyl group base. Examples of the substituent on the benzinyl group include a morpholinyl group and a piperidinyl group which are bonded from the ring carbon atom to the 3- or 4-position of the awkward ring. Suitable values for the in vivo hydrolysable guanamine containing a compound of the formula (I), such as Ν-C!·6 alkyl or ν, Ν-di-Cm alkyl decylamine such as Ν-methyl, Ν-B Base, propyl, hydrazine, hydrazine-dimethyl, hydrazine-ethyl-hydrazine-methyl or hydrazine, hydrazine-diethyl decylamine. Some of the compounds of formula (I) may have a palm center and/or a geometric isomerization center (Ε- and Ζ-isomers) and it is to be understood that the invention encompasses all such optical, diastereomeric effects with IB at inhibitory activity. Structures and geometric isomers. The present invention relates to any and all tautomers of a compound of formula (I) having IBAT inhibitory activity. -24 This paper size applies to China National Standard (CNS) A4 specification (210X 297 mm) 丄A7 ------------- V. Invention description (22) Also understand some of formula (1) The compound can exhibit a solvate as well as an unsolvated state such as a hydrated state. It will be understood that the present invention encompasses all such solvated states with debutatin inhibiting activity. The specific values are as follows. If this value is appropriate, it can be used for the definitions, patent claims or specific examples defined above or below.

Rv is hydrogen" R1 and R2 are C, -4 alkyl. R1 and R2 are both butyl groups. One of R and R is ethyl and the other is butyl. One of R and Ry is hydrogen and the other is a mercapto group.

Both Rx and Ry are hydrogen. Μ is -N-. Μ is -CH-. v is 〇 or 1. ν is 0 〇 R is C 1.4 alkyl. R3 and R6 are hydrogen. R4 is methylthio or bromo. R4 is a methylthio group. R4 is halo 'Cm alkyl or C, .4 alkyl S(0)a wherein a is 0. R4 is bromine, fluorenyl or sulfonium. R5 is a group of the formula (.1A) (as described above), wherein: X is -0-; ring A is a stupid group optionally substituted with one or more substituents selected from R17; _-25- paper The scale applies to China National Standard (CNS) A4 specification (210X 297 public) 1331143 A7 B7 V. Description of invention (23) η is 1; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; m is 0; R11 is formula ( The group of IB) (as described above); wherein: R12 is hydrogen; p is 1 or 2; R13 is hydrogen; q is 0; r is 0; R15 is a carboxyl group or a sulfo group; and R17 is a hydroxyl group. R5 is N-{(R)-a-[N-(carboxyindenyl)aminoindenyl]benzyl}aminodecylmethoxy or N-{(R)-α-[N-( 2-Sulphoethyl)aminoindenyl]-4-hydroxybenzyl}aminocarboxamidomethoxy. R5 is a group of formula (IA) (as described above), wherein: X is -0-; ring A is a phenyl group optionally substituted with one or more substituents selected from R17; η is 1; R7 is hydrogen; R8 is a mouse, -R9 is argon; m is 0; _-26-_ This paper scale is applicable to China National #准(CNS) A4 specification (210X297 mm) 1331143 A7

In R1: a group of formula (IB) (as described above) or a group of formula (1C) (as described above); R12 is hydrogen or C|-4, and P is 1 or 2; 'wherein R20 is hydroxy, Courtyard S (〇) a where &amp;

Rl3 is hydrogen or, as the case may be, substituted by R2G, Cl. 4 alkylaminocarbamyl, amine, benzyloxycarbonylamino or A. 0; R14 is hydrogen or hydroxy; q is 0; r is 0 or 1; R15 is a thiol or a contiguous group; R17 is a hydroxy group; and ring B is a phenyl group which is substituted on the slave by a group selected from R23, wherein r23 is a carboxyl group. R5 is 仏", 幻-^: -^, carboxymethylmethylaminomethyl benzyloxymethyl, N-{(R)-α-[N-(2-sulfo) Ethyl)aminomethylmercapto-4-ylhydroxymethyl}aminomercaptomethoxy, N-{(R)-a -[N-((S)-1-.*-2-hydroxyethyl Aminomethyl]benzyl}aminomethylindenyloxy, N_{(R)-a-[N-((S)-1-carboxyethyl)aminomethylindenyl]benzyl} Amino-based fluorenyloxy, N-{(R)-a: -[N-((S)-1·)propylamino)methylmercapto]benzyl}aminocarbazyl methoxy , N-{(R)-〇: _[ν·((R) -1-carboxy-2-indolyl-ethyl)aminomethylindenyl]benzyl}aminocarboxamylmethoxy , N-{(R)-a -[N-((S)-1-carboxy-2-aminomethylindenylethyl)aminomethylindenyl]nonyl}aminocarbonylcarbonyl ,&gt;1-{(11)^-[Chemical (carboxymethyl)amino fluorenyl]- ___-27- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1331143 A7 __B7 ______ V. INSTRUCTIONS (25) 4 -Amino-mercaptomethoxy, N-{(R)-a-[N-((S)-1-enylethyl)amine曱醯 ]]-4-hydroxybenzyl}aminomercaptomethoxy, Ν-Η R)- a -[N -((S)-1-carboxy-2-hydroxyethyl)aminomethylmercapto]-4-hydroxyl benzyl}aminomercaptomethoxy, N-{(R)-a-[N- (2-contigylethyl)aminoindenyl]hydrazino}aminocarbonylcarbonyl; ^-{(11)-〇:-[1^-((3)-1-carboxy- 2-( R)-hydroxypropyl)aminomethylindenyl]hydrazino}aminomethylindenyloxy, N-{(R)-a -[N-((S)-1-carboxy-2 -mercaptopropyl)aminocarbonyl]hydrazino}aminocarbonylcarbonyl, 1^-{(11)-〇:-[&gt;^((3)-1-carboxy-3- Nonylbutyl)amino fluorenyl]benzyl}aminocarboxylideneoxy, :^-{(foot)-〇:-[N-(1-(S)-1-carboxy-2- (S)-2-methylbutyl)aminomethylindenyl]nonyl}aminomethylcarbonyloxy, N-((R)-a-carboxy-4-hydroxyindenyl)aminopurine Methoxy, 1^-{(11)-oxime; -[1^-((8)-1-carboxy-4-aminobutyl)aminoindolyl] Anthraceneoxy, N-((R)-cι:-{N.[(S)-l-rebeyl-4-(nonyloxycarbonylamino)butyl]aminoindenyl}hydrazino)amino Mercaptomethoxy, N-[(R)- a-((S)-2-carboxypyrrolidin-1-ylcarbonyl)indolyl]aminocarboxamylmethoxy, N-{(R) -a -[N-(carboxymethyl)-N-decylamino Benzyl] benzyl}amino fluorenyl methoxy, N-{(R)-a -[N-( l-(R)_2-(R)_l- retino-1-yl-propyl- 2-amino)aminoindolyl]amino-aminomethylcarbonyloxy, N-{(R)-a-[N-(jingylmethyl)aminomethylindenyl] aryl) Base 曱 methoxy, N-((R)-a-carboxybenzyl)amino fluorenylmethoxy, N_ {(R)-a -[N-((S)-1-rebase -2-(R)-propylidene)aminocarbinyl]hydroxyl-yl}.Aminomethylmethoxy, N-UR)-^: ridyl-2-ylpropylpropylamine Alkyl]-4-ylhydrazino}amine-based oxime-based oxy group, N-{(R)-ck-[N-((S)-1- ethidylbutyl)amine group Base]_心经基_基) -28- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1331143 A7 B7 V. Description of invention (26) Amino-based methoxy group; ^-{(尺)-(^-[]^-((3)-1-carboxypropyl)aminoglycolyl]-4-carbylbenzyl}aminocarboxhydryloxy or 1^ -{(尺)-(^-[]^-((R)-l-decay-2-methylthioethyl)aminocarbonyl]_4·hydroxybenzyl anthranyl fluorenyl base. R is a group of formula (IA) (as described above), wherein: X is -〇; ring A is a phenyl group optionally substituted with one or more substituents selected from the group; η is 1; R7 is hydrogen; R8 is Hydrogen; R9 is hydrogen; m is 0; R11 is a group of formula (IB) (as described above) or a group of formula (ic) (as described above); wherein: R12 is argon or Cw alkyl; P is 1 or 2; R13 is argon or a Cw alkyl group substituted by r2G, wherein R2G is a hydroxyl group, an aminomethylguanidino group, an amine group, a fluorenyloxycarbonyl group, a Cm alkyl group S(0)a wherein a is 〇' or (Ci-4 alkyl) 3 Shi Xiyuan; R14 is hydrogen or hydroxy or CN6 alkyl; wherein R14 may be optionally substituted by one or more substituents selected from R2G; 丫 is (1^)(:( 0) - where 1^ is hydrogen; cj is 0; r is 0 or 1; -29- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1331143 A7 _-. B7 V. DESCRIPTION OF THE INVENTION (27) ''R is a fluorenyl or a phenyl group; Rl7 is a thiol group; and R20 is a hydroxy group; and ring B is substituted on a carbon by a group selected from R23 and optionally on carbon. Or a plurality of R24-substituted pyrrolidin-1-yl's wherein r23 is a carboxyl group and the caliper 24 is a trans-group. R5 is N-{( R)-a -[N-(carboxymethyl)aminoindenyl]fluorenyl}aminomethyl methoxy, N-{(R)-a -[N-(2- contylethyl) Aminomethylmercapto]_4_ via benzyl amide oxime methoxymethyl, N-{(R)-α-[N-((S)-l-- ethyl-2-ylethyl Aminomethylmercapto] fluorenyl}aminomethylcarbonyloxy, N_{(11)-〇!-[]^((8)-1-carboxyethyl)aminoindenyl] fluorenyl Aminomethylmercaptomethoxy, N-{(R)-a -[N-((S)-1-carboxypropyl)aminocarbamimidyl] fluorenyl}aminomethylindenyloxy ,1^-{(11)-〇:-[1^-((尺)-1-carboxy-2-methylthio-ethyl)aminomethylindenyl] fluorenyl}amino fluorenyl f-oxygen , N-{(R)-a -[1^-((8)-1-carboxy-2-aminoindolyl-ethyl)aminomethylindenyl]indenyl}aminocarboxamide Oxygen, sense {(11)-oxime: -[]^-(carboxyl)aminomethylmercapto]- 4-hydroxybenzyl}aminoindolyloxy, N-{(R)- o: -[1^-((3)-1-carboxyethyl)aminocarbamimidyl]-4-hydroxybenzyl}aminomethylindenyloxy, :^-{ (R)- a - [N-((S)-1-carboxy-2-hydroxyethyl)aminoindenyl]-4-hydroxyindolyl}aminomethylindenyloxy, N-{(R)-a -[ N-(2-sulfoethyl)aminomethylindenyl] }Aminomethylmercaptomethoxy,{{11]-«-[1^((3)-1-carboxy-2-(R)-hydroxypropyl)aminoindenyl]indenyl}amine Methyl methoxymethyl, N-{(R)-a -[N-((S)-1-carboxy-2-mercaptopropyl)amino fluorenyl] fluorenyl}aminomethyl fluorenyl曱oxy, N-{(R)-a -[仏((3)-1-carboxy-3-methyl)

Binding

-30- This paper scale applies to Chinese National Standard (CNS) A4 specification (2l〇x 297 mm) 1331143 A7 _____B7_ V. Description of invention (28) Butyl)aminomethylmercapto]hydrazino}amine Methoxy group, &gt;^-{(11)-〇:·· [N-(1-(S)-1-carboxy-2-(S)-2-mercaptobutyl)amino fluorenyl Amino group, an amine group, a methoxy group, an N-((R)-iZ-derivative-4-alkyl group), an amine group, a methoxy group, &gt; 1-{(1〇- 〇:-[1^-((3)-1-carboxy-4-aminobutyl)aminocarbonyl]hydrazino}aminocarbonyloxy, N-((R)-α- {N-[(S)-l-carboxy-4-(indolylcarbonylamino)butyl]aminomethylindenyl}benzyl)aminocarboxamylmethoxy, N-.[(R)- a-((S)-2-carboxypyrrolidin-1-ylcarbonyl)indolyl]aminomercaptomethoxy, N-{(R)-a-[N-(carboxymethyl)-N-曱 胺 胺 ] ] } } } } } 胺 胺 胺 胺 、 、 、 、 、, N-{ (R)- a -[N-( l-(R)-2-(R)-l-carboxy-1 -hydroxypropan-2-yl)amino fluorenyl] fluorenyl}aminomethyl fluorenyloxy, 1^-{(foot)-〇:-[]^-(sulfomethyl)amino Aminomethylcarbonyl, 1^-((11)-〇:-carboxymethyl)aminomercaptomethoxy :^· {(11)-〇:-[]^-((5)-1-carboxy-2-(11)-hydroxypropyl)aminocarbamimidyl]-4-hydroxyindenyl}amine hydrazine Mercaptomethoxy, N-{(R)-a-[N-((S)-l-carboxy-2-mercaptopropyl)aminoindolyl]-4-hydroxyindenyl}aminopurine Mercaptooxy group, &gt; 1-{(11)-〇:-[]^((8)-1-carboxybutyl)aminocarbamimidyl]- 4-hydroxyindenyl} Aminomethylmercaptopurine Oxy, N-{(R)-a-[N-((S)-1-carboxypropyl)aminocarbamido]-4-hydroxyindolyl}aminoindenyloxy, N- {(R)-α-[Να H)-l-carboxy-2-methylthioethyl)aminomercapto]-4-hydroxyindenyl}aminocarbinyloxy, 1^-{ (尺)-〇!-[1^-((8)-1-carboxypropyl)aminomethylindenyl]-4-hydroxyindolyl}aminomethylindenyloxy, n-{(R) - a -[N-{(S)-l-[N-((S)-2-hydroxy-1-carboxyethyl)aminoindolyl]propyl}aminoindolyl]hydrazino}amine Basementyl methoxy, N-{(R)-a -[2-(S)-2-(carboxy)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl Amino-based fluorenyl-oxygen-31 - This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1331143 A7 B7 V. Description of invention (29) Base, N-{ (R)-a -[2-(S)_2-(carboxy)azetidin-1-ylcarbonyl]fluorenyl}aminocarbonylcarbonyl, N_{(R)-a -[N-{ (S)_1-[N-((S)_1·carboxyethyl)aminoindolyl]ethyl}aminoindenyl]benzyl}aminoindolyloxy, N-{( R)-a -[N-((R)-1-carboxy-3,3-dimethylbutyl)aminoindenyl]hydrazino}aminocarbinyloxy, N-{(R )-a -[N-((S)-1-carboxy-3,3-dimercaptobutyl)aminoindenyl]benzyl}aminocarbinylmethoxy, N-{(11) -〇!-[]^-((11)-1-carboxy-3,3-didecylbutyl)aminomethylindenyl]-4-hydroxybenzyl}aminomercaptomethoxy, N -((R)-a -{N-[(S)_Bucarboxy-2-(trimethyldecyl)ethyl]aminoindolyl}-4-hydroxybenzyl)aminopurinyl Oxy or N-((R)- a -{N-[(R)-1-carboxy-2-(trimethyldecyl)ethyl]aminoindenyl}-4-hydroxybenzyl)amine The base is alkoxy. R5 is argon. R4 is a group of formula (IA). R5 is a group of formula (IA). It is therefore a further feature of the invention to provide a compound of formula (I) (as described above) wherein:

Rv is hydrogen; R1 and R2 are Ci.4 alkyl;

Rx and 1^ are all hydrogen; Μ is -N-; v is 0; R3 and R6 are hydrogen; R4 is halo, CU4 alkyl or Cm alkyl S(0)a wherein a is 0; R5 is formula ( IA) base (as mentioned above), where: -32- This paper scale applies to the China National Standard (CNS) A4 specification (210X 297 mm) 1331143 A7 B7 Five invention descriptions (30 X is; a phenyl group substituted with one or more substituents selected from Ri7; η is 1; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; m is hydrazine; R11 is a carboxyl group, a group of formula (ΙΒ) (as described above) Or a group of formula (1C) (as described above); wherein: R12 is hydrogen or c^.4 alkyl; P is 1 or 2; R13 is hydrogen or, as the case may be, R2. substituted (: .6 alkyl, Wherein R 2 Q is hydroxy, aminomethyl decyl, amine, benzyloxycarbonylamino, Cl 4 alkyl s(〇) a wherein a is 0, or (Cm alkyl) 3 decyl; R 14 is hydrogen or hydroxy Or C!·6 alkyl; wherein R14 may be optionally substituted with one or more substituents selected from R2G; Y is -N(Rn)C(0)- wherein Rn is hydrogen; q is 0 or 1; r is 0 or 1; R15 is a carboxyl group or a sulfo group; R17 is a hydroxyl group; and R2G is a selected hydroxyl group; and ring B is substituted on the carbon by a group selected from R23 and Optionally, on the carbon, one or more R24 groups are substituted for p to each bite-1 - or a butyl group; wherein r23 is • 33-

1331143 A7 ______ B7_ V. INSTRUCTION DESCRIPTION (31) The tempering group and R24 are a thiol group; or a pharmaceutically acceptable salt, solvate, solvate thereof or a prodrug thereof. It is therefore a further feature of the invention to provide a compound of formula (1) (as described above), which t:

Rv is hydrogen; R1 and R2 are both butyl;

Rx and Ry are both argon; Μ is -N-; ν is 0; R3 and R6 are hydrogen; R4 is bromo, methyl or methylthio; and R5 is equivalent {(11)^-[仏(carboxymethyl) Aminomethyl hydrazinyl] fluorenyl, N-{ (R) - α -[Ν-(2-sulfoethyl)aminoindenyl]-4-hydroxyindole Aminomethylmercaptomethoxy, N-{(R)-α-[N-((S)-l-carboxy-2-hydroxyethyl)aminomethylindenyl]indenyl}amino Mercaptomethoxy, N-{(R)-α-[N-((S)-l-carboxyethyl)aminocarbamimidyl]benzyl}aminocarbonylcarbonyl, N-{ (R)-a -[N-((S)-1-carboxypropyl)aminomercapto]hydrazino}aminomercaptomethoxy, N-{(R)-o: -[1 ^-((11)-1-carboxy-2-indolyl-ethyl)aminoindenyl]nonyl}aminodecylmethoxy, N-{(R)-a -[N- ((S)-1-carboxy-2-aminoindolyl-ethyl)aminoindenyl]hydrazino}aminomethylindenyloxy, 1^-{(11)-〇:-[ &gt;4-(carboxymethyl)amino fluorenyl]-4-hydroxyindolyl}aminomethylindenyloxy, N-{(R)-α-[1^-((5)-1 -carboxyethyl)aminomercapto]-4-hydroxyindenyl}aminomethylmercaptomethoxy, Ν α- This paper is also applicable to China National Standard (CNS) Α 4 specifications (210 X 297 mm) 1331143 A7 _ B7 V. Description of the invention (32 ) {(R)-a -[N-((S)-1-carboxy-2-hydroxyethyl)aminocarbenyl 4-hydroxyindenyl}aminocarbinylmethoxy, N-{(R)-o: -[Ν-(2-sulfoethyl)aminoindolyl]hydrazino}aminopurine Mercaptooxyl, 1^-{(11)-〇:_[1^-((3)-1-carboxy-2-(R)-hydroxypropyl)aminoindolyl]indenyl}amine醯 醯 曱 曱 、, N-{(R)-a _[N-((S)-bu carboxy-2-mercaptopropyl)aminomethyl hydrazino] fluorenyl}aminocarbinyl Oxyl, derivatized {(11)-^:-[^[-((5)-1-carboxy-3-methylbutyl)aminoindolyl]hydrazino}aminocarbinylmethoxy, 1^-{(11)^-[N-(1-(S)-1-carboxy-2-(S)-2-mercaptobutyl)aminoindolyl]nonyl}amino fluorenyl曱oxy, N-((R)-a-carboxy-4.hydroxyhydroxy)aminocarbonylcarbonyl, N-{(R)-a -[]^-((5)-1- Carboxy-4-aminobutyl)aminocarbyl];yl}aminomethylcarbonyl, N-((R)-a -{N-[(S)-1-carboxy-4- (Benzyloxycarbonylamino)butyl]aminomethylindenyl}nonyl)aminocarbonylcarbonyl, N-[(R)-a-((S)-2-carboxypyrrolidin-1- Aminocarbonyl) Oxy, N-{(R)-a-[N·(carboxyindenyl)-N-methylaminoindenyl]benzyl}aminoindenylmethoxy, N-{(R)- A-[N-( l-(R)-2-(R)-l-carboxy-1-hydroxypropan-2-yl)aminomethylindenyl]benzyl}aminodecylmethoxy, N -{(R)-〇:-[N-(sulfoindolyl)aminofluorenyl]benzyl}aminodecylmethoxy, N-((R)-a-carboxyindenyl)amine Methyl methoxymethyl, N-{(11)-^-[1^-((3)-1-carboxy-2-(11)-hydroxypropyl)aminoindolyl]-4-hydroxyl Benzyl}aminomethylindenyl foxy, N-{(R)-o: -[N-((S)-1-M*-2-mercaptopropyl ylaminomethylindenyl]-4 -hydroxybenzyl}aminoindenyloxy, &gt; 1-{(11)-1-[yi((3)-1-carboxybutyl)aminoindolyl]-4-hydroxybenzyl } Aminocarbonyl methoxy, :^-{(11)-〇:-[1^((3)-1-carboxypropyl)aminomethylindenyl]-4-hydroxyindenyl}amine Mercaptomethoxy, N-{(R)-α -[N- •35- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 mm) 1331143 A7 B7 V. Description of invention (33 ((R)-l-carboxy-2-methylthioethyl)aminomethylindenyl]-4-hydroxybenzyl}aminoindenyloxy, :^-{(11)-〇: -[ ((3)-1-carboxypropyl)aminomercapto]-4-hydroxyindolyl}aminomethylindenyl foxy, N-{(R)- &lt;2 -[N-{(S )-l-[N-((S)-2-hydroxy-1-carboxyethyl)aminoindenyl]propyl}aminomethylindenyl]benzyl}aminomethylindenyloxy, N -{(R)-a -[2-(S)-2-(carboxy)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}aminoindenyloxyl , N-{(R)-a -[2-(S)-2-(carboxy)azetidin-1-ylcarbonyl]benzyl}aminomethylindenyloxy, N-{(R) -a -[N-{(S)·卜[N-((S)- 1-carboxyethyl)amine aryl]ethyl}aminoindolyl]benzyl}aminoindenyl Oxyl, N-{(R)-a -[N-((R)-1-carboxy-3,3·dimethylbutyl)aminoindolyl]hydrazino}aminomethylcarbonyl , N-{(R)-a -[N-((S)-l-carboxy-3,3-dimethylbutyl)aminomethyl]]yl}aminomethyl methoxy义{(幻-〇-[1^-((11)-1-Resyl-3,3-dimercaptobutyl)aminoglycol]_4-yl-based}amino-based Methoxy, N-((R)-α; -{N-[(S)-l- stilbene-2·(三曱基石夕1)ethyl]amino fluorenyl}-4- Benzyl)amine-based methoxy or 1^-((11)-〇:-{&gt;1-[ (尺)-1-carboxy-2-(tridecyldecylalkyl)ethyl]aminomethylindenyl}-4-hydroxybenzyl)aminocarbamidomethoxy; or a pharmaceutically acceptable salt thereof, Solvate, Solvate of the Salt or Prodrug thereof / In another object of the invention, the preferred compound of the invention is Example 5, 6, 7, 9, 11, 14, 15, 26, 27, 28, 30 or 33 Any compound or a pharmaceutically acceptable salt, solvate thereof, solvate of the salt or a prodrug thereof. In another object of the present invention, the preferred compound of the present invention is an example or a pharmaceutically acceptable salt, a solvate thereof, a solvate of the salt or a prodrug thereof, or any of the above-mentioned paper sizes applicable to the Chinese National Standard (CNS). A4 size (210X297 mm)

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Mmr A7 B7 V. Description of the invention (34) Preferred object of the invention is related to a compound of formula (I) or a pharmaceutically acceptable salt thereof. Another object of the invention is to provide a compound of formula (I) or a medicament thereof Acceptable salts, solvates, solvates of such salts or prodrugs thereof' The method (wherein the variables are as defined in formula (I) 'unless otherwise stated) includes: Process 1): where X is _〇 For the compound of the formula _, -NRa- or _s_, 'to make the formula (Ila) or (Ilb)i:

(ΠΙ) where L is a replaceable group; Process 2): To make the acid of formula (IVa) or (IVb): -37- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 public) T33TU3 A7 B7 , invention description (35 H0

R· R2 .(IVa) H0

Or an activated derivative thereof; reacted with an amine of formula (V):

NH R ίο RJ (V); Process 3): For a compound of formula (I) wherein R11 is a group of formula (IB), a compound of formula (I) wherein R11 is carboxy is reacted with an amine of formula (VI) : R14 R 丨3

Y

d',L

JpNH R- (VI) Process 4) · For the compound of formula (I) wherein R4 and R5 are independently selected from carbon on one or more R17 groups, i.e., 6 alkylthio groups,乂113) or (Vllb) compound: •38- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 dongdong) T3nm A7 B7 V. Invention description (36) 5 Γ%//〇,V IU /k /S,N ,r丨

R2 Ry

L

R'

R

Mv (Vila)

R

R2 R1 M^pR, Ry mv (Vllb) wherein L is a replaceable group; reacts with a thiol of formula (VIII): ‘

Rm-H (VIII) wherein Rm is a Cw alkylthio group substituted with one or more R16 groups on carbon; Process 5): For a compound of formula (I) wherein R11 is a carboxyl group, formula (IXa) ) Compound:

(ΙΧπ) Do not use Vs R7 or formula (IXb\ compound deprotection 39 This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) Ι33ΙΓ43 A7 B7 V. Invention description (37)

Re,

—RR2, (R7-)v (IXb) wherein RP forms an ester together with the -0C(0)- group bonded thereto;

Rp. people

Y

-N

T Process 6): For the compound of the formula (I) wherein R11 is a group of the formula (IB) and R15 is a carboxyl group, a compound of the formula (Xa) is obtained: R'2 R10 n R8 R7 I L R9 I R14 R13 0

Deprotection of (Xa) or (Xb) compounds: R0 R 14 0 Υ

-40

This paper size applies to the Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1331143 A7 B7

T331 m - A7 ----------- B7 V. Inventive Note (39) ~·-- i) Convert a compound of formula (I) to another compound of formula ()) Π) Remove any Protecting group; in) forming a pharmaceutically acceptable salt, a solvate, a solvate of the salt or a prodrug thereof, and wherein L is a replaceable group, and an appropriate value of L is, for example, a halogen group. A hydrazinyl group such as a gas, a bromine, a decanesulfonyloxy group or a hydrazine-4-ylsulfonyloxy group. R forms a g with the 〇C(0)- group to which it is bonded. Preferably, RP is a benzyl group. Better RP is sulfhydryl. In another object of the invention, 'RP is Ci 6 alkyl. or phenyl C.. 6 alkyl, preferably Cl 4 alkyl or decyl, more preferably tert-butyl, methyl, ethyl or han. base. The specific reaction conditions of the above reaction are as follows. The bicyclic system of the present invention can be prepared according to the reaction scheme "or Ib. It is well known to those skilled in the art how to prepare an intermediate. The value of R4 or R5 in the following reaction scheme can be replaced by a suitable group. For example, to synthesize a compound of the formula (Ila), the following R4 in the reaction diagram is HX.

-42 - This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) Τ33ΓΓ43 A7 B7

T33im A7 B7 V. Description of invention (41)

(Η)

(CICO),, /-PrjNEt DMSO

R5 R4 Process 1): A compound of the formula (Ila) or (lib) can be combined with a compound of the formula (III) in the presence of a base such as an inorganic test such as sodium carbonate or an organic test such as Hunigs in a suitable solvent such as acetonitrile, dichloromethane or tetrahydrofuran. In the presence of 〇 ° C to reflux temperature, it is preferred to react near reflux or reflux. The compound of formula (III) is a commercially available compound, or it is known to the literature or prepared by procedures known in the art. Process 2) and Process 3) and Process 7): The acid and amine can be coupled together in the presence of a suitable coupling reagent. Standard peptide coupling reagents known in the art can be used as suitable coupling agents or, for example, carbonyldiimidazole and dicyclohexyl-carbodiimide, optionally in the presence of a catalyst such as dimethylaminopyridine or 4-indolepyridylpyridine In the presence of, depending on the situation, such as triethylamine, ρ than bite or 2,6-di-burning? It is carried out in the presence of a bite such as 2,6-dimercaptopine than *pyridine or 2,6-di-t-butylpyridine. Appropriate solvents include the size of the paper. Applicable to the Chinese National Standard (CNS) A4 specification (210 x 297 public) - 13-31Ί43 - A7 B7 V. Description of invention (42) Ethylamine, dioxane, benzene , tetrahydrofuran and dimethyl decylamine. The coupling reaction is preferably carried out at a temperature ranging from -40 ° C to 40 ° C. Suitable activated acid derivatives include hydrazine halides such as helium and activated esters such as pentafluorophenyl ester. The reaction of these types of compounds with amines is well known in the art, for example, it can be reacted in the presence of a base as described above and in a suitable solvent such as those described above. The reaction can be carried out at a temperature ranging from -40 to 40 °C. Compounds of formula (IVa) or (IVb) wherein X = -0-, -NRa, -S- can be prepared according to Reaction Scheme 2:

(Vila) -- (IVa)

NaC03

MeCN (IVc) (IVb) (Vllb)

NaC03

MeCN reaction diagram 2 wherein (Vila) and (Vllb) L is a replaceable group such as bromine, gas, fluorine, decanesulfonyl or toluenesulfonyl and its X is -0-, -S-, NRa ( For the case of -SO- and -S02-, the oxidation step of Process 1 is followed. The compounds of the formulae (IVa) and (IVb) wherein X is -SO- or -S02- can be prepared by oxidation of the compounds of the formulae (IVa) and (IVb) obtained by the reaction of Figure 2, wherein X is -S-. A compound of the formula (Va) or (Vb) wherein X is -CH2- and η is 1 can be prepared according to the reaction scheme 3. -45 - This paper size is applicable to China National Standard (CNS) A4 specification (210 X 297 mm) rmiw3 A7 B7 V. Description of invention (43

Those skilled in the art will be aware of compounds of the formula (Va) or (Vb) which are operable or have the above formula. Compounds of formula (XIa) and (XIb) can be prepared by the procedures described herein. And the system of η is 2 processes by the artist

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The compounds of the formulae (IVc), (V), (VI), (ΧΙΙ) and (VII) may be commercially available compounds, or they are known in the literature or may be prepared by standard methods of the art. Process 4): Compounds of the formula (Vila) and (Vllb) can be reacted with a thiol of the formula (νίπ) in the presence of an inorganic base such as sodium carbonate or an organic test such as Hunigs in the presence of a suitable solvent such as DMF or THF at 0 The reaction is carried out at a temperature ranging from ° C to reflux. -46 - This paper size is applicable to the S National Standard (CNS) A4 specification (210 X 297 mm). V. INSTRUCTIONS (44) Compounds of the formula (Vila) and (VIIb) can be prepared by the above formula (any procedure of the compound) Prepared, but wherein one of Han 4 and Rs is L. j (VIII) compound may be a commercially available compound, or it is known in the literature or may be prepared by standard methods of the art. Process 5) and Process 6): The esters of (IXa), (IXb), (Xa)A(Xb) can be protected under standard conditions (as described below), for example, they can be deprotected by sodium hydroxide in decyl alcohol at room temperature. The esters of the formulae (IXa), (ixb), (xa) and (Xb) can be produced by any of the procedures described above for the preparation of the compound of the formula (1), but the tRn*Rl5 is a Ci 4 alkoxycarbonyl group. It will be appreciated that certain of the various ring substituents in the compounds of this invention may be introduced by standard aromatic substitution reactions or by conventional functional group modifications prior to or after the above processes, and are included in the process objectives of the present invention. This reaction and upgrading include, for example, introduction of a substituent by an aromatic substitution reaction, a substituent reduction, a substituent alkylation, and a substituent oxidation reaction. The reagents and reaction conditions for this procedure are well known to the chemical industry. Specific examples of the aromatic substitution reaction include introduction of a nitro group using concentrated nitric acid, introduction of a mercapto group under Friedel Craft conditions using, for example, a phosphonium halide and a Lewis acid (such as aluminum trichloride); The base tooth and Lewis acid (such as aluminum trichloride) are introduced into the halogen group under the conditions of Friedrich Kreit. Specific examples of the reforming action include reduction of a nitro group to an amine group by, for example, catalytic hydrogenation with a nickel catalyst or treatment with iron under heating with hydrogen; oxidation of an alkylthio group to an alkylsulfinyl group or an alkylsulfonyl group. . It is also necessary to understand that in some of the reactions described herein, it is necessary/need to protect any sensitive groups of the compound A. Where protection is necessary or necessary, the appropriate protective effect is known to the skilled artisan. Especially during the synthesis of certain intermediates -47- This paper scale applies to the Chinese standard (CNS> A4 specification (210X2974^1 iJ3ll43 A7, --- B7______ V, invention description (45) ' ^ The protecting group can be used to protect the nitrogen at the 2' position of the benzothiazepine ring. Conventional protecting groups can be used according to standard practice (see, for example, Tw Green, Organic Synthetic Protecting Group, John Wiley and Sons, 1999). If the reactant contains a group such as an amine group, a carboxyl group or a hydroxyl group, it may be protected in some of the reactions described herein. Suitable protecting groups for an amine group or an alkylamino group are, for example, an anthracenyl group such as an alkano group such as B. A mercapto group, an alkoxycarbonyl group such as a methoxycarbonyl group, an ethoxycarbonyl group or a tert-butoxycarbonyl group; an aryloxycarbonyl group such as a decyloxycarbonyl group; or an aryl group such as a carbaryl group. The conditions must vary depending on the protecting group selected. Thus, for example, a mercapto group such as an alkanoyl group or an alkoxycarbonyl group or an aryl group can be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide such as lithium hydroxide or sodium hydroxide. In addition, the mercapto group such as the third butoxycarbonyl group can be borrowed It is removed by treatment with a suitable acid such as hydrochloric acid, sulfuric acid or wall acid or difluoroacetic acid, and an aryl methoxy group such as an oxime oxycarbonyl group can be removed by, for example, hydrogenation over a catalyst such as palladium on carbon, or borrowed. The Lewis acid is removed by treatment with, for example, fluoro(trifluoroacetate) boron. Suitable other protecting groups for the primary amine group are, for example, those which can be removed by treatment with an alkylamine such as diammonium propylamine or with a hydrazine. Suitable protecting groups for the group 26 are, for example, an indenyl group such as an alkyl group such as an ethyl group, an aryl group such as a fluorenyl group or an arylmethyl group such as a benzyl group. The deprotection conditions of the above protecting group must be selected. The protecting group may be different. Thus, for example, a fluorenyl group such as a fluorenyl group or an aryl group may be removed by, for example, hydrolysis with a suitable base such as an alkali metal hydroxide such as hydrogen peroxide or sodium hydroxide. The base can be removed by, for example, hydrogenation over a catalyst such as palladium on carbon. Suitable protecting groups for the thiol group are, for example, a cyclyl group such as a base such as nitrox-48-

This paper is again applicable to China National Standard (CNS) A4 specification (210 X 297 mm) 1331143 V. Inventive Note (46) Sodium or B, which is removed by sodium hydrolysis, *, X 6 base, or for example The second butyl group is removed by, for example, treatment with an acid such as an organic acid such as trifluoroacetic acid, or may be removed, for example, by, for example, a catalyst such as a hydrogenation. The protecting group can be removed in any aspect of the synthesis J/L / by Tian P White &amp; using conventional techniques known in the chemical arts. As described above, the human and the sigma defined in the present invention have IBAT inhibitory activity. Such values can be used, for example, by using in vitro sputum. The assay was used to evaluate the effect of bile acid uptake in (7) octa-transfected cells (Srmth L., price-jones M. j,

Hugnes KT and Jones NR a. Fighting 8 7 from 'A., Journal of Biomolecular Screening, 3, 227-230) or in vivo by studying the effects of radiolabeled bile acids in mice/rats (Lewis MC·, Briedaddy L.EjR〇〇tc,],]up ^ η% 36, 1098-1105). A further pharmaceutical composition according to the invention provides a pharmaceutical composition comprising a compound of the formula (1), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable diluent or Carrier. The composition may be in a form suitable for oral administration, such as a tablet or capsule, a parenteral injection (including intravenous, subcutaneous, intramuscular, intravascular or perfusion) sterile solution, suspension or emulsion, topically administered. A suppository for ointment or cream or rectal administration. In general, the above compositions can be prepared in a conventional manner using conventional excipients. The compound of the formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof, is generally administered to a warm-blooded animal in a dosage unit in the range of 5 5 mg per square meter of the animal. That is, about 〇〇 2_1〇〇 mg / kg, preferably 0.02-50 mg / kg dose, and generally provide therapeutic effective 丄 five, invention instructions (47 agents summer. Early dosage form such as key #丨# ..v agent Or the knee capsule generally contains, for example, 1-250 mg of active ingredient. It is better to use the daily dose of 力·50 mg/kg, especially 0. Bu 10 mg/kg. Another purpose Φ , —Γ /± m A dose range of 0.02-20 mg/kg can be used. However, the dose of sputum must follow the treatment host, the specific route of administration, and the severity of the disease to be treated. Thus, the optimal dose can be treated by any particular patient. The invention provides a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof, as defined herein, for the prophylactic or therapeutic treatment. The use of blood animals such as humans. A compound defined therein, or a pharmaceutically acceptable salt thereof, a solvate of a solvate thereof, or a prodrug thereof, is an effective octabutin inhibitor, and accordingly has a disease state associated with a hyperlipidemia condition. This object provides the use of a compound of formula (]), or a pharmaceutically acceptable salt, solvate, solvate thereof, or a prodrug thereof, as defined herein, for pharmaceutical use. According to another feature of the invention, there is provided a Use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, solvate thereof, or a prodrug thereof, for the production of an IB AT inhibitory effect in a warm-blooded animal such as a human. 'Another feature according to the invention provides a Use of a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, as defined herein, for the treatment of a hyperlipidemia condition in a warm animal, such as a human. Provided a compound of formula (I), or a pharmaceutically acceptable salt thereof, as a solvate thereof, a solvate thereof, or a prodrug thereof, for use in the manufacture of warm blood Treatment of lipid metabolism disorders in humans such as humans and ___ -50- This paper scales Common Chinese National Standard (CNS) A4 specifications (210X297 mm) 1331143 A7 B7 V. Description of invention (48) Such as hyperlipidemia, high tris Glycerolemia, hyperlipoproteinemia (high LDL), very high lipoproteinemia (high VLDL), hyperlactinemia, low lipoproteinemia, hypercholesterolemia, hyperlipoproteinemia, and low A pharmaceutical use of a disorder of alpha lipoproteinemia (low HDL). According to another feature of the invention there is provided a compound of formula (丨) as defined herein, or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof or Prodrugs are used in the treatment of different clinical conditions such as atherosclerosis, arteriosclerosis, rhythm irregularities, hypertensive thrombosis, vascular function, endothelial dysfunction, cardiac disorders, coronary heart disease, heart in warm-blooded animals such as humans. Vascular disease, myocardial infarction, angina pectoris peripheral vascular disease, cardiovascular tissue such as heart inflammation, valve 'vascular distribution, arteries and veins, aneurysm, stenosis, restenosis, vascular plaque, vascular lipid Mark, white blood cells, a single cell and / or macrophage infiltration, intimal thickening, thinning arterial media, infections and surgical trauma and vascular thrombosis pharmaceutical use of shock, stroke and transient-ischemic. According to another feature of the invention there is provided a compound of the formula 'π" as defined herein, a pharmaceutically acceptable salt, solvate, solvate of the salt thereof or a prodrug thereof for use in the manufacture of arteriosclerosis in a warm-blooded animal such as a human Medical use of coronary heart disease, myocardial infarction, angina pectoris, peripheral vascular disease, stroke, and short-term anemia. According to still another feature of the present invention, there is provided a method for producing a sputum inhibitory effect in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of the formula (1) or a pharmaceutically acceptable salt or solvate thereof. , a solvate of its salt or a prodrug thereof. Another feature of this object in accordance with the present invention is to provide a temperature to be treated -51 - 1331143 A7

A compound of the formula (I) or a solvate thereof or a prodrug thereof which is highly lipid-effective in the treatment of a salt such as a human. The method of diagnosing comprises administering to the animal a pharmaceutically acceptable salt, solvate, and another object according to the present invention, the extra-column # e ^J force characteristic system provides a therapeutic animal such as a human Treatment of disorders of lipid metabolism and such as hyperlipidemia, vocal triglyceride" by lipemia, high rock lipidemia (high LDL), very "lipoproteinemia (still VLDL), high lactobacillus, low A method of lipoproteinemia, hypercholesterolemia, hyperlipoproteinemia, and low alpha lipoproteinemia (lower job) disorders comprising administering to the animal an effective amount of a compound of formula (1) or a pharmaceutically acceptable amount thereof a salt, a solvate, a solvate thereof, or a prodrug thereof. According to another aspect of the present invention, there is provided a method for treating different clinical conditions such as atherosclerosis and arteriosclerosis rhythm in a warm-blooded animal such as a human to be treated. Incomplete, thrombosis, vascular dysfunction, endothelial dysfunction, cardiac disorders, coronary heart disease, cardiovascular disease, myocardial infarction, human pain, peripheral blood tube disease, cardiac management, such as heart inflammation, flap , vascular distribution, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fat marks, white blood cells, infiltration of single cells and/or macrophages, thickening of the intima, thinning of the middle layer of the arteries, infection and surgical trauma And a method for vascular embolization, stroke, and transient hemorrhagic shock, comprising administering to the animal an effective amount of a compound of the formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof or a prodrug thereof Another feature of the invention is to provide a method for treating arteriosclerosis, coronary heart disease, myocardial infarction, angina pectoris, peripheral vascular disease, stroke and transient hemorrhagic shock in a warm-blooded animal, such as a human, to be treated, ___ -52 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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An effective amount of a compound of the formula (i) or a pharmaceutically acceptable salt thereof, a solvate of a salt thereof, or a prodrug thereof, is administered to the animal. It can be seen that IB AT inhibitors are potentially useful for the treatment and/or prevention of gallstones. A further feature of this object according to the invention is to provide a method of treating gallstones in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a solvate, a salt thereof, or a prodrug thereof. The dose required for therapeutic or prophylactic treatment must vary depending on the treatment host's route of administration and the severity of the disease to be treated. "A unit such as 〇.丨_5〇 mg/kg, preferably 0.1-10 mg/kg can be used. dose. The IBAT inhibitory activity as defined herein may be used in the form of monotherapy or may include one or more other substances and/or treatments in addition to the compounds of the invention. This combination therapy can be achieved by administering the individual components of the treatment, either sequentially or separately. According to the purpose of the present invention, there is provided a pharmaceutical composition comprising a compound of the formula (I), or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof, and other IBAT-inhibiting substances as defined above, and A combination of other lipid-lowering agents for the treatment of hyperlipidemia. In another object of the present invention, the compound of the formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof or a prodrug thereof may be combined with an HMG Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, The solvate, the solvate of the salt thereof or a prodrug thereof is administered in combination. Suitable HMG Co-A reductase inhibitors, their pharmaceutically acceptable salts, solvates, solvates of the salts thereof or prodrugs thereof are known in the art as statins. In particular, Stadin is fluvastatin, lovastatin, Pavasta; Ding-53- This paper wave scale applies Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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1331143 A7 ______B7 V. Description of invention (51) (pravastatin), 希ivasta, din (simvastatin), atorvastatin; din (atorvastatin), chromivastatin (cerivastatjn), borvasda, din (bervastatin ), daivastatin, mevasatin, and (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(曱基硕醯) Amino]pyrimidin-5-yl](3 R,5 S)-3,5-dihydroxyhept-6-enoic acid (rosuvastatin) or a pharmaceutically acceptable salt thereof, solvent a compound, a salt thereof, a solvate or a prodrug thereof. In particular, statin is a vasstatin or a pharmaceutically acceptable salt, solvate, solvate of the salt thereof or a prodrug thereof. More specifically, Star &gt; D is (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[indolyl(fluorenylsulfonyl)amino] shouting - 5-Based](3R,5S)-3,5-dihydroxyhept-6-enoic acid or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof. More specifically, Statin is a Rosvastatin calcium salt. In still another object of the present invention, the compound of the formula (1) or a pharmaceutically acceptable salt, solvate thereof, solvate thereof or a prodrug thereof may be combined with an HMg C0_A reductase inhibitor or a pharmaceutically acceptable salt or solvate thereof The solvate of the salt or its prodrug and/or bile acid binder is administered in combination, thereby avoiding the possible risk of excess bile acid in the colon caused by inhibition of the ileal bile acid delivery system. Excessive bile acid in the visceral content can cause diarrhea. Accordingly, the present invention also provides a method of treating a side effect such as dysentery in a patient, which comprises a compound of the formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof, during the treatment. The HMG Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate of the salt thereof or a prodrug thereof will reduce the supply of bile = acido-54-

1331143 A7 B7 V. INSTRUCTIONS (52) Addition of endogenous cholesterol to a lipid-lowering effect in combination with a compound of the formula (丨) or a pharmaceutically acceptable salt thereof, a solvate, a solvate thereof, or a prodrug thereof . Suitable bile acid binders for this combination therapy are resins such as cholestyramine and cholesipol. One advantage is that the bile acid binder dose can be maintained at a lower dose than the therapeutic dose that treats cholesterolemia in a monotherapy comprising only a bile acid binder. Low-dose bile acid binders can also avoid any possible side effects caused by poor tolerance of the patient to the therapeutic dose. Therefore, in another feature of the invention, there is provided a method of producing an IBAT-inhibiting effect in a warm-blooded animal, such as a human, in need thereof, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutical acceptable thereof. a salt, a solvate, a solvate thereof, or a prodrug thereof, and an effective amount of a HMG Co-A reductase inhibitor or a pharmaceutically acceptable salt, solvate, or a solvent thereof, simultaneously, sequentially or separately Compound or its prodrug. Therefore, in another feature of the invention, there is provided a method of inhibiting the effect produced in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt or solvate thereof. 'The solvate of the salt or its prodrug and the simultaneous, sequential or separate administration of bile acid viscosity. Therefore, another feature of the present invention is a method for producing an IBAT inhibitory effect in a warm-blooded animal such as a human in need of treatment, ~ Λ w 右田田木万, including a compound of formula (I) or a pharmaceutically acceptable compound thereof, a pharmaceutically acceptable salt thereof, a solvate thereof, or a prodrug thereof, and Simultaneously, according to the order or separately, an effective amount of HMG Co-A reductase inhibitor or its medicinal section, solvate-55-

1331143 5 invention description (A7 B7 53 substance, a solvate of the salt thereof or a prodrug thereof, and simultaneous, sequential or separate administration of a bile acid binder. Therefore, in another feature of the invention, a temperature is provided for treatment A method for treating a southern lipidemia in a blood animal, such as a human, comprising administering to the animal an effective compound of formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and An effective amount of an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof, is administered sequentially or separately. Therefore, in another feature of the present invention, A method of treating hyperlipidemia in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate thereof, a salt thereof, or a mixture thereof Prodrugs and simultaneous, sequential or separate administration of an effective amount of a bile acid binder. Therefore, in another feature of the invention, there is provided a method for treating hyperlipidemia in a warm-blooded animal to be treated = human, including The The animal is administered a compound of the formula (1) or a pharmaceutically acceptable salt thereof, a solvate thereof, a salt thereof, or a drug thereof, and an effective amount of HMG Co-A is administered simultaneously, sequentially or separately. a reductase inhibitor, or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof, and a bile acid binder simultaneously, sequentially or separately. According to still another object of the present invention, A pharmaceutical composition comprising a compound of the formula (1), a pharmaceutically acceptable salt thereof, a solvate, a solvate thereof, or a prodrug thereof, and an HMG Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, a solvate thereof, Salt solvate or its prodrug' and medicinal acceptable

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5. Description of the Invention (Sexual diluent or carrier. According to still another object of the present invention, a 捭 &amp; M p 楗 楗 种 医 , , , , , , , , , , 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其 或其a compound of 4, a solvate of the salt thereof or a peony thereof, and a bile acid, B&gt; carrier. Ze. d and a therapeutically acceptable diluent or a pharmaceutical composition according to the present invention, comprising a compound of formula I, or a pharmaceutically acceptable salt, solvate thereof, solvate thereof or a prodrug thereof And an HMG Co-A reductase inhibitor, or a pharmaceutically acceptable disolvate thereof, a solvate thereof, or a prodrug thereof, and a bile acid, and a pharmaceutically acceptable diluent or carrier. According to another aspect of the present invention, there is provided a kit comprising the compound of the formula (j): or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a hydrazone thereof, and HMG Co-A reductase inhibition Or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof. Or a pharmaceutically acceptable salt prodrug thereof and a bile acid binder according to still another object of the present invention or a pharmaceutically acceptable salt thereof according to the present invention, further comprising a kit comprising a solvate of the formula (1), The solvate of the salt thereof or a system thereof provides a kit comprising a solvate of the formula (I), a solvate of the salt thereof or a crude drug thereof, and an HMG Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, a solvent a solvate of a salt thereof or a prodrug thereof, and a bile acid binder. According to a further aspect of the invention there is provided a kit comprising: a) a compound of formula (1), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, in a first unit dosage form;

(1) 1143

a hmg c "reductase inhibitor or a pharmaceutical thereof in an early dosage form", a granule, a solvate thereof, or a prodrug thereof; and c) for containing the first and second dosage forms A container device. According to a further aspect of the invention there is provided a kit comprising: a) a compound of formula (1) or a pharmaceutically acceptable compound thereof, a solvate thereof or a prodrug thereof in a first unit dosage form; b) A bile acid binder in a second unit dosage form: and a pharmaceutically acceptable salt, c) a container device comprising the first and second dosage forms. According to a further aspect of the invention there is provided a kit comprising: a) a compound of the formula (1) or a pharmaceutically acceptable over-solvate thereof, a solvate of a salt thereof or a prodrug thereof in the first unit dosage form; b) a _c〇_A reductase inhibitor in the second unit dosage form or a bile acid binder of the third unit dosage form; and d) for containing the first, second and third A container device of a dosage form. According to still another object of the present invention, a kit is provided, comprising: a) a compound of the formula (1) or a pharmaceutically acceptable sleep solvate thereof, a solvate of the salt thereof or a prodrug thereof, and a pharmaceutically acceptable release agent or carrier; ' &lt; twins b) in a second unit dosage form a HMG c〇_A reductase inhibitor or a therapeutic agent thereof; a receptive salt, a solvate, a solvate thereof, or a prodrug thereof; and a reagent device for containing the first and second dosage forms According to still another object of the present invention, there is provided a kit comprising: a) a compound of the formula (1) or a pharmaceutical hydrazine salt thereof in the first unit dosage form, -58-

L33U43 A7

a solvate, a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable diluent or carrier; b) a bile acid in a second unit dosage form; and c) a container device comprising the first and second dosage forms. According to still another object of the present invention, there is provided a kit comprising: a) a compound of the formula (1) or a pharmaceutically acceptable salt thereof, a 'mixture of a compound', a solvate thereof or a prodrug thereof, and a pharmaceutically acceptable substance in a first unit dosage form Receptive diluent or carrier;)/HMG Co-A reductase inhibitor in a unit dosage form or a pharmaceutically acceptable salt, solvate, solvate thereof or a prodrug thereof; c) in a third unit a bile acid binder in the dosage form; and d) a container device comprising the first 'second and third dosage forms. According to another aspect of the present invention, there is provided a compound of the formula (I) or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof or a prodrug thereof, and a hmg Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof A solvate, a solvate thereof, or a prodrug thereof, for use in the manufacture of a medicament for producing an IBAT-inhibiting effect in a warm-blooded animal such as a human. According to another aspect of the invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and a bile binder for use in the manufacture of a warm animal such as a human 〖BAT inhibition effect of the use of medicine. According to still another feature of the present invention, there is provided a compound of the formula, or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and a HM(} Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof Solvate, its salt-59- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)

1331143 5. The use of a solvate or a prodrug thereof and a bile acid binder of the invention (57) for the manufacture of a medicament for producing an IBAT-inhibiting effect in a warm-blooded animal such as a human. According to another feature of the present invention, there is provided a compound of the formula (1), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, as a Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof, A solvate, a solvate thereof, or a prodrug thereof, for use in the manufacture of a medicament for the treatment of a warm-blooded animal such as a human: a hyperlipidemia condition. According to still another feature of the present invention, there is provided a compound of the formula (1) or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and a bile acid binder for use in the treatment of a warm-blooded animal such as The use of medicine for humans with high lipid and blood diseases. According to still another feature of the present invention, there are provided two compounds of the formula (1) or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and an HMG Co-A reductase inhibitor or a pharmaceutically acceptable salt thereof And a solvate of a salt thereof or a prodrug thereof and a bile acid binder for use in the manufacture of a medicament for treating a hyperlipidemia condition in a warm-blooded animal such as a human. Further, according to the present invention, a combination therapy is provided, comprising administering a therapeutically effective amount of a compound of the formula (1) or an acceptable salt, a solvate, a solvate thereof or a pharmaceutically acceptable salt thereof to a warm-blooded animal such as a human. A pharmaceutically acceptable diluent or carrier, and at the same time 'sequential or two: two effective amount of HMGC〇-A reductase inhibitor or its pharmaceutically acceptable solvate or its prodrug and optionally According to still another feature of the present invention, a combination therapy is provided, including the need for the ________-60-book paper, the wealthy family, Lai CNS) A-tigrid (21GX 297 public 1 1331143 five, invention description (58) treatment A warm-blooded animal, such as a human, administered an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable diluent or carrier, depending on the condition, and , or sequentially or in combination with an effective amount of a bile acid binder and, optionally, a pharmaceutically acceptable dilution or carrier. According to the present invention, a combination therapy is provided, including a warm-blooded animal such as a human in need of such treatment. Injecting an effective amount A compound or a pharmaceutically acceptable di-salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof, and optionally a pharmaceutically acceptable diluent or carrier, and simultaneously, sequentially or separately administered HMG Co-A Reductase inhibitor or a pharmaceutically acceptable herbicide thereof, a solvate thereof, a solvate thereof, or a prodrug thereof, and optionally a pharmaceutical; a receptive diluent or carrier, and a bile acid binder simultaneously, sequentially or separately And a pharmaceutically acceptable diluent or carrier, as appropriate. According to still another object of the present invention, there is provided a combination therapy comprising administering an effective amount of a compound of formula (1) or a medicament thereof to a warm-blooded animal, such as a human, in need of such treatment. Receptive salts, solvates, solvates of the salts thereof or prodrugs thereof, and optionally pharmaceutically acceptable diluents or carriers, and simultaneously, sequentially or separately, are administered one or more agents selected from the group consisting of: &gt; CETP (cholesterol ester transfer protein) inhibitors, for example, w〇〇〇/38725, page 7, line 22 to page 10, line 17, and are incorporated herein by reference; &gt; cholesterol chemist antagonists such as Kenting bites Ketones such as SCH 5823 5 and described in US 5,767,115, which is incorporated herein by reference; &quot; MTP (microsomal transfer protein) inhibitors such as those described in Science, 2 8 2, 7 5 1 · 54, 1998, It is also for reference in this article; -61 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 public) Gutter 13311143 A7 _B7__ V. Description of invention (59) &gt; Fibric acid derivatives such as Coro fiber Clofibrate, gemfibrozil, ferlfibrate, ciprofibrate and bezafibrate; &gt; final acid derivative For example, alkali acid (niacin), acipimox and pentaerythritol nicotinate; &gt; phytosterol compounds such as stanols; &gt; probucol &gt;Anti-obesity compounds such as orlistat (EP 129, 748) and sibutramine (GB 2, 184, 122 and US 4, 929, 629); &gt; antihypertensive compounds such as angiotensin converting enzyme Inhibitor, angiotensin II receptor antagonist 'adrenergic blocker, alpha-renal Blockers, stone adrenergic blockers, mixed/adrenergic blockers, adrenergic stimulators, calcium channel blockers, diuretics or vasodilators; &gt;insulin;&gt; Containing gHbenciamide, tolbutamide; &gt;metformin; and/or &gt;arabinose; or a pharmaceutically acceptable salt, solvate, solvent thereof a pharmaceutically acceptable diluent or carrier thereof, or a prodrug thereof, as appropriate. Specific ACE inhibitors, pharmaceutically acceptable salts, solvates, solvates of the salts thereof or prodrugs thereof (including active metabolites) which may be used in combination with a compound of formula (J) include, but are not limited to, the following compounds: Acepin (acecepri丨), ____-62- This paper scale applies to China National Standard (CNS) VIII 4 & (21〇χ297 mm)--- 1331143 A7 _______ B7 V. Description of invention (6〇) Alatupopril, ahi〇pril calcium, ancovenin, benazepril, stupapine hydrochloride, benazeprilat, clumsy Benz〇ylcapt〇pril, captopril, cartepine-cysteine, cartepine-glutathione, ceranapril, ceranapri丨, color Ceronapdl, Cilazapril, cilazaprilat, deLapril, delapine-diacid, inaipril, enalaprilat, innapri丨, epicaptopril ' fahimisin (f〇r〇Xymi Thine), fosfenopril, fosenoprii 'fasenpine sodium, fosinopril, fahepine sodium, fahsbit (f〇sin〇priiat), fashibi acid (fosinopdlic Acid), gyicopril 'hemyphril 4 (hem〇rphin_ 4), edrapril, imidapril, indolapril, 朵"Dorabit ( Ind〇iapriiat), libenzapnl, iisinoprii, a, 枸杞B, mixanpril, moexipril, m〇exiprilat, Mo Vapteltipril, muracin A, cytochrome B, cytochrome C, pentopril, perin (j〇prii), bite bit (perindoprilat), special Pivai〇prH, piva〇prii quinapril, n-quine hydrochloride, 4Ubitriiat, ramipril, lamipid Ramipriiat), spirapril: spiroxine hydrochloride, spiraprilat, spiropril, spirulina hydrochloride, temocapine (t Em〇capril), temocarpine salt S夂 salt, teprotide, trandolapril, anti-multi-63- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1331143 A7 __B7 V. Description of invention (61) trandolaprilat, utibaprU, zabicipril, zabiciprilat, zofenoprii and oxazolol (zofenopdlat). Preferred ACE inhibitors for use in the present invention are ramipril, ramirrUat, 丨isin〇pril, enalapril and enaiapriiat. Further preferred ACE inhibitors for use in the present invention are ramjprii and ramiprilat. Preferred angiotensin 11 antagonists, pharmaceutically acceptable salts, solvates, solvates thereof, or prodrugs thereof, which may be used in combination with a compound of formula (I), include, but are not limited to, the following compounds: Kendasa Candesartan, candesartan cilexetii, sarsartan, valsartan, irbesartan, tassartan 'telmisartan and eprsartan. A particularly preferred angiotensin II antagonist or a pharmaceutically acceptable derivative thereof for use in the present invention is candesartan and candesartan cilexetil. In another object of the present invention, a compound of the formula () or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt, a solvate thereof, or a prodrug thereof, may be compatible with a PPAR alpha and/or tau agonist or a pharmaceutically acceptable drug thereof. The salt, solvate, solvate of the salt thereof or a prodrug thereof is administered in combination. Suitable PPAR alpha and/or 7 agonists or their pharmaceutically acceptable salts, solvates, solvates of the salts thereof or prodrugs thereof are well known to those skilled in the art. These include those described in W〇01/12187, W0 01/12612, WO 99/62870 'W0 99/62872 'W0 99/62871 'W0 98/57941 ' WO 01/40170, Journal of Medicinal Chemistry, 1996, 39, 665 For treatment patents -64- This paper scale applies Chinese National Standard (CNS) Α4 specification (210X 297 dongdong) 1331143 A7 _____B7_____ V. Invention description (62) Professional opinion, 10(5), 623-634 (especially Compounds listed on page 634 of the patent application, and the medicinal chemistry journals, the compounds described in U.S. Patent No. 4, the disclosure of which is incorporated herein by reference. Particularly good ppAR 〇; and / or 7 agonists are WY-14643, ci〇fibrate, fenofibrate, bezafibrate, Gw 9578, 牦Troglitazone, pioglitaz〇ne, rosiglitazone, eglitaz〇ne, proglitazone, BRL-49634 'KRP- 297 &gt; JTT-501 - SB 213068 'GW 1929 &gt; GW 7845 'GW 0207 ' L-796449 &gt; L- 165041 and GW 2433. Particularly preferred ppar 〇; and/or r agonist is (s)-2-ethoxy-3-[4-(2-{4-methanesulfonyloxyphenyl)ethoxy] Propionic acid and its pharmaceutically acceptable salts. Further suitable pi&gt;AR alpha and/or agonists are ΝΝ622/Ragagiitazar and bms 298585. It is therefore a further feature of the invention to provide a method of producing an IBAT-inhibiting effect in a warm-blooded animal, such as a human, in need of treatment, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate of a salt thereof or a prodrug thereof, and an effective amount of a PPAR and/or 7 agonist or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof or a prodrug thereof, simultaneously, sequentially or separately . It is therefore a further feature of the invention to provide a method of treating high lipid A in a warm-blooded animal, such as a human, in need thereof, comprising administering to the animal an effective amount of a compound of formula (I) or a pharmaceutically acceptable salt, solvate thereof, a solvate of a salt thereof or a prodrug thereof, and an effective amount of a ppar ^ and/or r agonist or a pharmaceutically acceptable salt thereof, a solvate thereof, or a salt thereof, in a simultaneous, sequential or separate manner - 65- 1331143

DESCRIPTION OF THE INVENTION A7 B7 agent or a prodrug thereof. According to another aspect of the present invention, there is provided a pharmaceutical composition comprising the formula (1) = in combination with a pharmaceutically acceptable salt, a solvate thereof, a solvate thereof, a pharmaceutically acceptable salt thereof, and a PPAR alpha and/or r agonist Or a pharmaceutically acceptable salt thereof, a cold form, a solvate thereof, or a prodrug thereof, and a pharmaceutically acceptable diluent or carrier. . According to another aspect of the present invention, there is provided a kit comprising: a compound of the formula pharmaceutically acceptable salt, solvate, solvate thereof or a prodrug thereof, and a PPAR alpha and/or r agonist or a medicament thereof An acceptable salt, solvate, solvate thereof, or a prodrug thereof. According to still another object of the present invention, there is provided a kit comprising: a) a compound of formula (1) or a pharmaceutical thereof in a first unit dosage form Receptive salt 'solvate, solvate of the salt thereof or a prodrug thereof; b) PPAr α and/or sputum agonist or its pharmaceutically acceptable salt, solvate in its second unit dosage form a solvate or a prodrug thereof; and c) a container device comprising the first and second dosage forms. According to a further object of the present invention, there is provided a kit comprising: a) a compound of formula (j), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof thereof, in a first unit dosage form and a pharmaceutically acceptable diluent or carrier; b) a pPar 〇: and/or a agonist or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof; c) providing a container device containing the first and second dosage forms. According to another feature of the present invention, there is provided a compound of the formula (?) or a pharmaceutical product thereof ________-66- The paper size is 圉 China National Standard (CNS) Α 4 specification (210Χ 297 mm)

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1331143

Receptive salt, solvate, solvate of the salt thereof or a prodrug thereof, and ppAR α and/or 7 agonist or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a pharmaceutically acceptable compound thereof It is used for medicines that suppress the effect of sputum in warm-blooded animals such as humans. According to still another feature of the present invention, there is provided a compound of the formula (1) or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof or a prodrug thereof, and a ppAR α and/or r agonist or a pharmaceutical acceptable thereof A salt, a solvate, a solvate thereof, or a prodrug thereof for use in the manufacture of a medicament for the treatment of a warm-blooded animal such as humans = lipidemia. According to still another feature of the present invention, there is provided a combination therapy comprising administering to a warm-blooded animal, such as a human, in need of such treatment an effective amount of a compound of formula (1) or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof or a prodrug and optionally a pharmaceutically acceptable diluent or carrier, and an effective amount of a PPAR alpha and/or r agonist or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable salt, or a pharmaceutically acceptable salt, A solvate of the salt or a prodrug thereof, and optionally a pharmaceutically acceptable diluent or carrier. In addition to its therapeutic use in medicine, a compound of the formula or a pharmaceutically acceptable salt thereof, a solvate of a salt thereof, or a prodrug thereof, is used in the development of in vitro and in vivo test systems for the evaluation of IB AT inhibitors in laboratory animals such as cats, The effects of dogs, rabbits, monkeys, rats, and mice can also be used as a physiological tool in the standardization and as part of a new therapeutic agent. Many of the intermediates described herein are novel and thus may be further provided as features of the present invention. For example, the compounds of the formulae (IXa), (IXb), (xa) and (Xb) exhibit IBAT inhibitory activity when tested in the above in vitro assay and thus

1331143 A7 ______ B7 V. Description of the invention (65) is a further feature of the invention. A still further feature of the present invention is to provide a compound of the formula (IXa), (IXb), (Xa) or (Xb), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof. A further feature of the invention provides a pharmaceutical composition comprising a compound of formula (IXa), (IXb), (xa) or (Xb) as defined herein or a pharmaceutically acceptable salt, solvate or solvate thereof Or a prodrug thereof and a pharmaceutically acceptable diluent or carrier. A further feature of the invention provides a compound of formula (IXa), (ixb), (Xa) or (Xb) as defined herein, or a pharmaceutically acceptable salt, solvate thereof, solvate thereof, or a prodrug thereof Use in a method for preventing or treating a warm-blooded animal such as a human. A further feature of the present invention provides a compound of the formula (IXa), (IXb) '(xa) and (Xb), or a pharmaceutically acceptable salt, solvate thereof, a solvate thereof, or a prodrug thereof, as defined herein Use. A further feature of the invention provides a compound of formula (IXa), (IXb) '(Xa) or (Xb) as defined herein or a pharmaceutically acceptable salt thereof, a solvate, a solvate thereof, or a prodrug thereof The use of a medicine for producing an IB AT inhibitory effect in a warm-blooded animal such as a human. A further feature of the invention provides a formula (IXa), (IXb) '(xa) or (Xb) sigma as defined herein, or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof Use for the manufacture of medicines for the treatment of hyperlipidemia in warm-blooded animals such as humans. Another feature of the present invention is to provide a warm-blooded animal such as a human in need of treatment. The paper is applicable to the Chinese national standard (C^^210X 2 3~------ 1331143 A7 B7. The method of producing an inhibitory effect of IB AT in (66) includes administering to the animal an effective amount of a compound of the formula (IXa), (IXb), (Xa) or (Xb), or a pharmaceutically acceptable salt or solvate thereof A solvate of a salt thereof or a prodrug thereof. Another feature of the present invention is to provide a method for treating hyperlipidemia in a warm-blooded animal, such as a human, in need of treatment, comprising administering an effective amount of the formula (IXa) to the animal, a compound of (IXb), (Xa) or (Xb), or a pharmaceutically acceptable salt thereof, a solvate thereof, a solvate thereof, or a prodrug thereof. Among other pharmaceutical compositions, processes, methods, uses, and pharmaceutical manufacturing characteristics described above Other and preferred embodiments of the invention described herein may also be applied. EXAMPLES The invention will now be illustrated by the following non-limiting examples in which the standard techniques known in the art and the similar techniques described in the examples are appropriate Can also use 'and unless There are instructions, otherwise: (1) The evaporation is carried out in a vacuum by a rotary evaporator and the termination procedure is carried out after removing residual solids such as a desiccant by filtration; (ii) all reactions are in inert gas and ambient temperature (generally 18_25t) : range) by HPLC-grade solvent under anhydrous conditions unless otherwise stated; (iii) Column chromatography (by rapid procedure) is carried out on silica gel 4〇-63 μm (Merck); (iv) Yield For illustrative purposes only and not necessarily the maximum achievable value; (v) The final product structure of formula (I) is confirmed by nuclear (generally proton) magnetic resonance (NMR) and mass spectrometry techniques; the magnetic resonance chemical shift value is based on deuterated Cd3〇 d (unless otherwise stated) is expressed in <5 grade (low magnetic field ppm from tetradecyl decane); proton data is quoted unless otherwise stated; spectrum is in Varian Mercury-300 L·------- 69- The paper size is suitable for S s material (CNSyA Vision (21G 297 297 public) 1331143 A7 B7 V. Invention description (67) MHz 'Varian Unity plus-400 MHz ' Varian Unity plus-600 MHz or Recorded on a Varian Inova-500 MHz spectrometer; and the number of peaks is shown below: s, single peak; d, Double peak; dd, bimodal doublet; t, triplet; tt, trimodal triplet; q, four peaks; tq, four peaks of three peaks; m, multiple peaks; br, broad peaks; LCMS in Waters ZMD, LC column Recorded on X Terra MS C8 (Waters) to configure the HP 11 00 MS-detector detection of the diode array; mass spectrometry (MS) (loop) is recorded on the VG Platform II (Fisons instrument) to configure the pole HP 1100 MS-detector detection of the array; unless otherwise stated, the mass ion referred to is (MH+); (vi) Unless otherwise specified in the specification, the analytical high performance liquid chromatography (HPLC) is used. Prep LC 2000 (Waters), Kromasil C8, 7 micron (Akzo Nobel); MeCN and deionized water 100 mM ammonium acetate with appropriate composition as mobile phase; (vii) Intermediates are generally not fully characterized and purity is borrowed Thin layer chromatography (TLC), HPLC, red ray (IR), MS or NMR analysis evaluation; (viii) use of sodium sulfate as a desiccant for solvent dehydration; (ix) when using "ISOLUTE" column Means a column containing 2 grams of silicone, which is contained in a 6 ml disposable syringe and a porous disk with a diameter of 54 angstroms. ISOLUTE" is available from International Adsorbent Technologies; "ISOLUTE" is a registered trademark; (X) The following abbreviations are used in the foregoing or following: DCM di-methane; DMF N,N-dimercaptoamine; TFA trifluoroacetic acid ; _-70-_ This paper size applies to China National Standard (CNS) A4 specification (210X297 mm)

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1331143 V. Description of the invention (booklet) TBTU o-benzotris-l-yl-N,N,N,,N, tetramethyl choline tetrahedral acid salt;

Ethyl acetate; and MeCN acetonitrile. Example 1 LJ-diporo.-3,3-dibutyl--5-styl-7-side dim (carboxy^棊_1-linked methylmercapto-1benzyl fluorenyl)-2·ΐ4 ^π二L· 2,5-stupid ρ 塞 二ρ丫hine 1,1-oxo-3,3-dibutyl-5·styl-7-bromo-8-carboxymethoxy_ 2,34,5_ Tetrahydro-indole, 2,5-benzoxazepine dioxime (method 2; 〇〇2 gram, 3 71*1〇.5 mol) in DCM (4 ml) solution Add (R)_a_[decath(t-butoxycarbonylindolyl)aminomercapto]benzylamine (Method 5; 0.013 g, 4.82*10·5 mol) and indolinylmorpholine (0.015 ml, 1.48) * 10. 4 m). The mixture was stirred for 5 minutes and then TBTU (0.015 g, 4.82*1 〇·5 mol) was added. The reaction mixture was stirred overnight and TFA (1·5 mL) was added. After 1 hour, the solution was diluted with a solution and the solvent was removed under reduced pressure. The residue was purified with EtOAc EtOAc EtOAc EtOAc. NMR (400 MHz, DMS0-d6) 0.60-0.80 (m, 6H), 0.80-1.60 (m, 12H), 3.30 (dd (AB), 1H), 3.45 (dd (AB), 1H), 3.85 (brs , 2H), 4.70 (d (AB), 1H), 4.75 (d (AB), 1H), 5.60 (d, 1H), 6.90-7.50 (m, 12H), 8.00-8.10 (m, 1H), 8.55 (d, 1H). Example 2 - 1,1-Dihalo-3.3-dibutyl-5-styl-7-methylthio-8-(1^-{(10-^-"1^-(carboxymethyl)amine曱醯 芊 芊 芊 丨 某 某 某 ) ) ) ) ) ) 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本 本

Four gas-1,2,5-bute well g plug two p丫 wide 1,1·dioxo-3,3·dibutyl s |, ^ base _7· thiol-8-carboxymethoxy 2,3,4,5-wind-(1)-stupid and B-plug II 丫 丫 (method 3; gas base 3. gift 5 m) in DCM (4 ml) solution added (r) butoxy A few f methyl)amino, alkyl] * amine (method 5; (third 4.54 * ^ Moer) and N-methyl mala (10) 15 ml, i48M 〇 _ 4 g, mixture tax mixed for 5 minutes followed by TBTU (〇〇15g, 4 82*ι〇., ear). The reaction mixture was stirred overnight and added with fa fa (15 ml). After the solution was diluted with a solution, the residue was removed by subtraction. Injury: HPLC was carried out using Me(3)/acetic acid (4) material to dry to dryness, and the title compound was obtained as a white solid 〇〇 18 g (82%). NMR (C, · DMS0-d6) 0.65-0.80 (m, 6H), 0.85- 1.60 (m, 12H), 2.10 (s, 3H), 3.65 (dd (AB), 1H), 3.75 (dd (AB), 1H), 3.85 (brs, 2H), 4.65 (d (AB, 1H), 4.75 (d (AB), 1H), 5.60 (d, 1H), 6.55 (s, 1H), 6.90-7.50 (m, 11H), 8.45 (d, 1H), 8.50-8.60 (m, 1H). 3 1:1-dioxo 2:3·diding _5•Ping _7_ bromo·8_(N_((R)_a 碏醯Base) riding _ 曱酽 曱酽 I · · } } } 胺 胺 胺 胺 胺 胺 · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · · Indole due to 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-carboxyloxy-2,3,4,5_tetraar-1,2,5 Add 2_{[(2R)_2_amino 2 (2) to a solution of benzopyrazine (Method 2; 〇〇5 gram, 9 27* 1 〇-5 mol) in DME (6 ml) 4 hydroxy phenyl) ethyl amide] amino} ethyl benzoic acid (method 6; 〇 _ 〇 33 grams, 1.2 〇 * 1 〇 · 4 moles) and Ν-methyl morpholine (0.041 ml, 3.72 * 10 · 4 moles. Mixing mixture _____ -72· This paper scale applies to China National Standard (CNS) Α4 specification (210X 297 public) 1331143 A7 B7 V. Invention description (70 10 minutes followed by TBTU (0.039 g, 1.21) * 4.4 摩尔). The reaction mixture was stirred overnight and the solvent was evaporated under reduced pressure. The residue was purified using EtOAc EtOAc (EtOAc) 53%). NMR (400 MHz, DMSO-d6) 0.60-0.80 (m, 6H), 0.80-1.60 (m, 12H), 2.40-2.60 (m, 2H), 3.10-3.50 (m, 2H), 3.85 (brs, 2H) ), 4.70 (d (AB), 1H), 4.75 (d (AB), 1H), 5.25 (d, 1H), 6.70 (s, 1H), 6,75 (s, 1H), 6.85-7.80 (m , 10H), 8.15-8.25 (m, 1H), 8.45 (d, 1H)S 9.40 (brs, 1H) 〇 Example 4 1,1-dioxo-3,3-dibutyl-5-momo- 7-Methylthio-8-fN-UR)- α - "Ν-Κ S)-Bucarboxy-2-mercaptoethyl) Aminomethyl hydrazino 1 decyl guanylaminomethyl methoxy group ^ One / Qiao - four gas - ^ ^ - benzopyrazine dipyridyl 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-carboxy oxime 2,3,4,5-tetrahydro-1,2,5-benzoxaindole (method 3; 0.050 g, 0.099 mmol), N-[(2R)-2-amino group -2-Phenylethylindenyl]-o-(t-butyl)-L-serine tert-butyl ester (Method 14; 0.042 g, 0-120 mmol) and N-decylmorpholine (0.033) A solution of ML, 〇. 299 mL of DCM (4 mL) was stirred at RT for 10 min then TBTU (0.041 g, 0.128 mmol). After 8 hours, the conversion was completed; m/z: 839.7. TFA (2 mL) was added and the reaction mixture was stirred for 12 h. The solution was transferred to a separating funnel and washed twice with water and then concentrated. The residue was purified by preparative HPLC using 40-60%EtOAc /EtOAc. NMR (400 MHz, DMSO-d6): 0.60-0.80 (6H, m), 0.85-1.60 (12H, m), 2.10 (3H, s), 3.40-3.65 (2H, m), 3.85 (2H, -73 - This paper scale applies to China National Ladder (CNS) A4 specification (210 X 297 mm)

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% 1331143 A7 B7 V. INSTRUCTIONS (71) brs), 4.10-4.20 (1H, m), 4.70 (1H, d (AB)), 4.75 (1H, d (AB)), 5.70 (1H, d), 6.60 (1H, s), 6.85-7.50 (12H, m), 8.50 (1H, d), 8.60 〇H, d) ; m/z : 839.7. Example 5 1.1-Dioxo-3.3-dibutyl-5-styl-7-methylthio-8-(1^4(1〇-^4]^-((S)-l-carboxyethyl Amino fluorenyl 1 fluorenyl}aminomethylmercaptomethyl)-2,3,4,5-tetrahydro-1.2.5- benzopyrazine quinone 1,1-dioxo- 3,3-Dibutyl-5-styl-7-indolethio-8-|^-((11)-fluorenyl-carboxybenzyl)aminocarbonylcarbonyl]-2,3,4 , 5-tetrahydro-1,2,5-benzopyrimidine (Example 25; 0.055 g, 0.086 mmol), L-proline 1,1-dimethylethyl ester hydrochloride ( A solution of 0.017 g., 0.098 mmol/N-Mercaptomorpholine (0.028 mL, 0.254 mmol) in DCM (5 mL) was stirred at RT for 10 min then TBTU (0.033 g, 0.103 mmol) After 16 hours, the conversion was complete; m/z: 767.4. TFA (2.5 mL) was added and the reaction mixture was stirred for 2 hours. The solution was diluted with toluene and then concentrated. The residue was used for preparative HPLC using 40-60% MeCN/O .lM ammonium acetate gradient buffer was purified as a solution to give the title compound y 〇 〇 44 g (72%). NMR (4 〇〇 MHz): 0.70-0.85 (6H, m), 0.90-1.70 (12H ,m), 1.30 (3H,d),2.1〇(3H, s), 3 .95 (2H, brs), 4.25-4.40 (1H, m), 4.60 (1H, d (AB)), 4.65 (1H, d (AB)), 5.60 (1H, s), 6.60 (1H, s) , 6.95-7.50 (11H, m); m/z 767, 4. Example 6 1-dioxo-3.V dibutyl-5-phenyl-7-indolethio- 8-(N"(TM - --"N-dicarboxylic acid, two amines, amine fluorenyl 1 fluorenyl} amine, a certain methyl group, a methyl group) II I__________-74- This paper ruler is not enough (CNS) A4 specification (21GX 297 public) Love) 'binding

% 1331143 A7

231^.,5-tetra_^1,2.5_mosaquinone dioxeine 1,1-dioxo-3,3-dibutyl·5_phenyl·7_methylthio·8_[Ν ( (ιι)_α carboxy group) Amino fluorenyl methoxy]-^ 斗^tetrahydro-^ Hong 笨 并 嘧 实例 实例 实例 实例 (example 25; 0.055 grams, 0.086 millimoles), butyric acid 2 _ Amino. 丨 山 dimethyl ethane hydrochloride (2S) _ (0 〇 2 gram, 〇 1 〇 2 mmol) and Ν methyl morpholine (0.035 ml, 〇 316 316 m) A 2DCM (5 mL) solution was stirred on the crucible for 10 minutes then TBTU (0.036 g, 0.112 mmol) was added. After 19 hours, add 2-amino-1,1-didecylethyl ester hydrochloride (2S)_(〇〇2〇克' 0.102 mmol), N-methylorene (0.035) ML, 0.316 millimoles) and TBTU (0.036 grams, 0.112 millimoles). The conversion was completed after 68 hours; m/z. 7 81 _ 5. Add TF A (2 mL) and the reaction mixture for 7 hrs and then add TF A (2 mL). The reaction was completed after 1 8 hours. The solution was transferred to a separating funnel and washed twice with water and then concentrated. The residue was purified by preparative HPLC using 40-60% EtOAc EtOAc (EtOAc: EtOAc) 0.65 (3H, t), 0.65-0.80 (6H, m), 0.85-1.75 (14H, m), 2.10 (3H, s), 3.80 (2H, brs), 3.95-4.10 (1H, m), 4.65 ( 1H, d (AB)), 4.75 (1H, d (AB)), 5.65 (1H, d), 6.55 (1H, s), 6.85-7.50 (12H, m), 8.50 (1H, d), 8.60 ( 1H, d) ; m/z 781.5. Example 7 1,1-dioxo-3,3-dibutyl-5-phenyl-7-indole-8-indole-((indol-1-carboxy-2-methylthioethyl)amine 1,1,3,4.5-tetrahydro-1,2.5-mosacene dioxeine 1,1-dioxo-3,3- Dibutyl-5-styl-7-methylthio-8-[义((11)-〇:-carboxy-75- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1331143

Benzyl)aminomercaptomethoxy]-2,3,4,5-tetrahydro-1,2,5-benzoxaindole (Example 25, 0.055 g, 0.086 mmol) , S-mercapto-L-cysteine second butyl g (Pestic·Sci· ; EN ; 45 ; 4 ; 1995 ; 357-362 ; 0.020 g '0.105 mmol) and N-methyl? A solution of EtOAc (5 mL) was stirred at RT for 10 min then TBTU (0.036 g, 0.112 m). After 19 hours, additional s-mercapto-L-cysteine tert-butyl ester (0.020 g, 0.105 mmol) was added as 'N-mercaptoline (0.035 ml '0.3 17 mmol) and TBTU ( 0.036 g, 0.112 mmol. Conversion completed after 68 hours; m/z: 811.6 (M-l)_. TFA (1_5 mL The reaction was completed after 18 hours. The solution was transferred to a separating funnel and washed twice with water and then concentrated. The residue was purified by preparative HPLC using 40-60% EtOAc EtOAc EtOAc (EtOAc) :0.65-0.80 (6H,m),0.85- 1.60 (12H, m), 1.85 (3H, s), 2.10 (3H, s), 2.60-2.80 (2H, m), 3.80 (2H, brs), 4.20 -4.35 (1H, m), 4.65 (1H, d (AB)), 4.75 (1H, d (AB)), 5.65 (1H, d), 6.55 (1H, s), 6.85-7.50 (12H, m) , 8.45 (1H, d), 8.65 (1H, d). Example 8 1,1-dioxo-3.3-dibutyl-5-styl-7-methylamido-8-(]^-{(10-〇!-"&gt;^ ((S)-l -carboxy-2-amine, a mercaptoethyl)aminocarboxamyl hydrazide, a methyl methoxyl group, -2.3.4.5-tetrahydro-1,2,5-methane Geng N-mercaptomorpholine (0.034 ml, 0.3 14 mmol), TBTU (0.033 g, 0.103 mmol) and L-aspartic acid 1, bisdimethylethyl ester monohydrochloride-76 - ----- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm) Mountain 1143

(0.02 gram, 0.093 millimolar) sequentially added u-dioxo 3 dibutyl succinyl I methylthio-8-[N-((R)W)-based methoxyl base Oxy]-2,M,5_tetrahydro-!,2,5-benzopyrene, aglycone (Example 25; 〇〇5 gram, 毫mmol) DCM (5 mL) solution in. After 2 small 0, there is still the starting material and N-methyl chlorate (0.035 ml, 〇.314 mmol) and tbtu (〇03 mmol). After 12 hours, the transformation The solution is diluted with water (about 5 ml) and then extracted with diethyl ether three times. The combined organic phases are dehydrated and concentrated with sulphuric acid, and the residue is dissolved in DCM (5 ml) and TF A (2 · 5 ml) The mixture was stirred for 2 hours in the mixture. The solution was transferred to the same funnel and washed with water and then concentrated. The residue was purified using preparative HpLC using 40-60% MeCN/O.lM ammonium acetate gradient buffer as the eluent. The title compound 〇 〇 22 g (37%) was obtained as a white solid. NMR (400 MHz, DMSO-d6): 0.06-0.80 (6H, m), 0.80-1.60 (12H, m), 2.10 (3H, s) , 2.25-2.70 (2H, m), 3.80 (2H, brs), 4.35-4.45 (1H, m), 4.65 (1H, d (AB)), 4.75 (1H, d (AB)), 5.60 (1H, d), 6.55 (1H, s), 6.70-7.60 (14H, m), 8·45 (1H, d), 8.55-8.70 (1H, m); m/z: 810.5. Example 9 _1, 1-II Oxo-3,3-dibutyl-5-mercapto-7-methylthio-8-(yi{(10-(^4^[-(__2-sulfoethyl)amino)indolyl i_4 _hydroxy fluorenyl} 2-,3,4,5-tetrahydro-1,2,5-methyl-co-glyoxime ammonium salt using the procedure of Example 3 from l,1-dioxo-3, 3-dibutyl-5-phenyl-7-nonylthio-8-carboxy-methoxy-2,3,4,5-tetraar-1,2,5-benzopyrimidine Method 3; 43 mg, 0.085 mmol: starting synthesis of the title compound. The solvent was evaporated and the crude product was purified by preparative HPLC (C8 column, 50×250 mm) for 3 hours to apply ___-77- paper scale to Chinese national standard (CNS) A4 size (210 X 297 mm) binding

1331143 A7 _____B7 V. Inventive Note (π ) Purification with 1^6(:^/0.11^ ammonium acetate gradient buffer (40/60 to 60/40) as the eluent. Freeze-dried to obtain 38 mg of the title compound (57%) NMR (400 MHz) · 0.8 (t, 6H), 1.0-1.2 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H), 1.55-1.7 (m, 2H), 2.1 (s, 3H), 2.8-3.0 (m, 2H), 3.55-3.7 (m, 2H), 3.95 (brs, 2H), 4.6 (ABq, 2H), 5.35 (s, 1H), 6.6 (s, 1H), 6.75 (d, 1H), 7.05 (t, 1H), 7.15-7.4 (m, 7H), 8.15 (t, 1H) ; m/z : 763 〇 Example 10 14-dioxo- 3,3-dibutan-5-phenyl-7-methylthio-"N-(_基基基基) 基 醯 1-4 1-4-hydroxy-ammonium-methyl fluorenyl fluorenyl )_L3,4,5-tetrahydro-p- and Pf-di- 1,1-dioxo-3,3-dibutyl-5-indolyl-7-indolethio-8-[&gt;1 -((11)*^-carboxy-4-hydroxyindenyl)aminoindolyloxy]_2,3,4,5-tetrahydro-indole, 2,5-benzopyranin (Example 18; 50 mg '0.076 mmol) dissolved in DCM (4 mL). EtOAc (3 mg, EtOAc &lt;RTI ID=0.0&gt; (20 microliters, 0.15 millimoles) And tbTU (30 mg, 0.091 mmol), 3 hours later, add DMF (2 ml) and obtain a clear solution. Add the third butyl glycinate (0.04 mmol), 2,6·lutidine (0.15 mmol) and TBTU (2 X 0.03 mmol) and the mixture was stirred for a further 3 hours. The reaction mixture was concentrated and taken between KHS04 aqueous solution (〇·〇5M, pH=1) and EtO Ac (2 X 20 ml) The organic phase is washed with brine, dehydrated and concentrated to give the titled compound of the title compound of the butyl ester of the title compound: M/z: 769 and 786 (M+ 18 (Νϋ4+)) » Add DCM (4 ml) and TFA (1.5 ml) The mixture was stirred for 2 hours and then concentrated and used as a preparative hplc in a C8 column (50 Χ 250 mm). \^匚1^/0.11^ ammonium acetate gradient buffer (20/80 to 50/50) -78- The paper scale is applicable to the Chinese National Standard (CNS) Α 4 specification (2 〇Χ 297 public love 7 1331143 A7 _B7________ 5, invention description (76) as a solution purification. Lyophilization gave 52% (28 mg) of the title compound. NMR (400 MHz): 0.8 (t, 6H), 1.0-1.2 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H), 1.55-1.7 (m, 2H), 2.1 (s, 3H), 3.9 (ABq, 2H), 3.95 (brs, 2H), 4.6 (ABq, 2H), 5.45 (s, 1H), 6.6 (s, 1H), 6.75 (d, 2H), 7.05 ( t,1H), 7.15-7.4 (m,7H) ; m/z : 730 (M+18 (NH4+). Example 11 1.1-diode-3,3-dibutyl-5-stupyl-7- Methylthio-8-(仏{(1〇-£^-"1^-((S)-l-carboxyethyl)amine, a methylmercapto-1-4-hydroxyindenylamine group Oxy)-2,3.4,5-tetrahydro-1.2.5- benzopyroxypyrene using the procedure of Example 10 from 1,1-dioxo-3,3-dibutyl-5-phenyl -7-decylthio-8-[yi((尺)-6^-carboxy-4-hydroxybenzyl)aminocarbamidomethoxy]-2,3,4,5·tetrahydro-1, 2,5-benzopyridinium (Example 18; 50 mg, 0.076 mmol) and L-alanine t-butyl ester hydrochloride, starting synthesis of the title compound M/z: 783 and 800 (M+ 18 (NH4+)). EtOAc (EtOAc: EtOAc) -1.2 (m,6H), 1.25-1.4 (m, 2H) , 1.3 (d, 3H), 1.4-1.5 (m5 2H), 1.55-1.7 (m, 2H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.35 (q, 1H), 4.6 (ABq, 2H), 5.45 (s, 1H), 6.6 (s, 1H), 6.75 (d, 2H), 7.05 (t, 1H), 7.15-7.4 (m, 7H) ; m/z : 744 〇 Example 12 1.1- Dioxo-3,3-dibutyl-5-styl-7-indolethio-8-(N-UR)--丨Μ- ίβ)-!-xiang-2-hydroxyethyl)amine曱醯 曱醯 1-4 鼗 1-4 } } } } } } - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - - Applicable National Standards for Competing Countries (CNS) A4 Specifications (210 X 297 mm ^ — ' 1331143

Using the procedure of Example 10, 1-di-deutero-3,3·dibutyl_5_phenyl-7-methylthio-8-[N-((R)-a-monoyl_4· Aminomethylmercaptofoxy]_2.3.4.5-tetrahydro-1'2,5-benzoxanthium oxazepine (Example 18; 5 〇 mg, 〇 (4) mM) And o-(t-butyl)-L'serine tributyrate hydrochloride. The title compound was synthesized. The intermediate ester was confirmed. m/z: 755. Hydrolysis and purification by preparative HPLC to give 19 mg title Compound (33% yield). M/z: 743 (M+l). NMR (400 MHz): 0.8 (t, 6H), l. 〇.L2 (πΐ5 6Η), 1.25-1.4 (m, 2H) S 1.4-1.5 (m, 2H), 1.55-1.7 (m, 2H), 2.1 (s, 3H), 3.65-3.8 (m, 2H), 3.95 (brs, 2H), 4.33 (t, 1H), 4.6 (ABq, 2H), 5.5 (s, 1H), 6.6 (s, 1H), 6.75 (d, 2H), 7.05 (t, 1H), 7.15-7.4 (m, 7H) 〇' Example 13 LJ-diox Generation-3,3-dibutyl_-5-phenyl-7-methylthio(R)-α-ΓΝ-yieldethyl)aminomethylmercaptopurine]amine a certain methoxyl 13.4.5- Tetrahydro-1,2,5-mosphthoquinone as 1,1-dioxo-3,3-dibutyl-5-phenyl-7-decylthio-8- [&gt; 1-((11)-〇:-carboxyindenyl)aminocarbinyl Methoxy]-2,3,4,5-tetrahydro-1,2,5-phenyl and 17-dioxadecane (Example 25; 50 mg, 0.078 mmol) was dissolved in 3 mL of DCM. Butyl ammonium taurate (88 mg, 0.236 mmol) and the mixture was stirred for 30 minutes. TBTU (30 mg, 0.093 mmol) was added and the mixture was stirred overnight. The solution was concentrated and purified by preparative HPLC on C8 column ( 50 X 250 mm) was purified as an eluent using ]^01^/0.1]^ ammonium acetate gradient buffer (20/80 to 60/40). Lyophilized to obtain 43 mg of the product mixture, which was then subjected to flash chromatography (5 g). Purified by gradient elution with 3-20% MeOH in DCM. The title compound was collected and concentrated. MeOH and water and lyophilized to obtain 17 mg (29% ___-80- This paper scale applies to Chinese National Standard (CNS) A4 size (210 X 297 mm) 1331143 A7 — B7 V. Description of invention (78) Yield) NMR (400 MHz) ·· 0.8 (t, 6H), 1.0-1.2 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H), 1.55-1.7 (m, 2H), 2.1 (s, 3H), 2.85-3.0 (m, 2H), 3.5-3.7 (m, 2H), 3.95 (brs, 2H), 4.6 (ABq, 2H), 5.45 (s, 1H), 6.6 (s, 1H), 7.05 (t, 1H) ), 7.15-7.45 (m, 10H) ; m/z : 747. Example 14 LJ-di-gas-3.3-dibutyl-5-styl-7-decylthio πη_ π LLS)· 1-. Carboxy-2彳R)-hydroxypropyl)aminocarbamyl 1芊 丨蚣奚 碑 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- 1- Benyl-7-methylthio-8-[N-((R)-a-benzylidene)aminocarbamoyloxy]-2,3,4,5-tetrahydro-1,2 5-Benzothiaphthyl dioxime (Example 25; 50 mg, 0.078 mmol) was dissolved in 1 mL; [] MF and 1 mL DCM. Add o-butylidene-(L)-threonate tert-butyl ester (22 mg; 0.095 mmol) and N-methylmorpholine (17 μl, 〇.154 mmol) and stir the mixture 20 minutes. Add TBTU (30 ml, 0.093 mmol) and &gt; trough solution for 2 hours and concentrate. D C Μ (20 ml) was added and the solution was washed with 1 ml of saline, dehydrated and concentrated to 3 ml. Confirm intermediate vinegar; m/ ζ : 853. Add TFA (0.5 mL) and stir the solution overnight. Additional 5 ml of TFA was added and after 3 hours, the mixture was concentrated and preparative HPLC was used on a C8 column (50 X 250 mm) using MeCN/O.lM ammonium acetate gradient buffer (20/80 to 60/40) as the eluent. Purification "Freeze-drying gave 61% yield (36 mg) of title compound. NMR (400 MHz): 0.8 (t,6H),0,9 (d,3H), 1.0-1.2 (m,6H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H), 1.55 -1.7 (m, 2H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.15-4.25 (m, 1H), 4.35 (d, 1H), 4.6 (ABq, 2H), 5.65 (s, 1H ), 6.6 (s, 1H), 7.05 (t, 1H), 7.1 (d, 2H), 7.15-7.4 (m, 6H), 7.5 -81 - This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1331143

(d, 2H) im/z : 741 ° Example 1 5 1,1-O-oxo-3,3-butyl-5-phenyl:_2-indolethio-8-(:^-{( ]?)_(3;-|^-U^LlLAA^2··!············································· 5-tetrahydro-1.2·5- laughing and soul diterpene M-dioxo-3,3·dibutyl_5_ stupyl_7_methylthio_8_[N_((R)_a ·carboxyindole Aminomethyl methoxy] 2,3,4,5-tetrahydro-i,2,5-phenyl and oxazepine (Example 25; 50 mg, 〇.078 mmol) Dissolved in 2 ml of DMFt. Add (L)-tridecyl citrate (20 mg; 〇·〇 95 mmol) and Ν·曱基吗 (17 μl '0.154 mmol) and mix for 2 minutes. Add τΒτυ (30 ml, 0.093 mmol) and stir the solution overnight. Add methylmorpholine (8 μL, 0.078 mmol) and TBTU (3 Χ 5 mg, 0.047 mmol) and stir the mixture overnight and concentrate the β residue by flash chromatography (2 g) using EtOAc:hexane (3: 7) Purified as a solution. The collected fractions were washed with 5 〇 / 〇 NaHC 〇 3 (1 〇 ml), (mm KHS 〇 4 (15 ml) and brine, dehydrated and condensed. The third compound of the title compound was confirmed. m/z : 812 (M+ 18 (NH4+)). Add DCM (4 ml) and TFA (1_5 mL) and mix the mixture overnight. Concentrate and prepare Hplc on a C8 column (50 X 250 mm) using MeCN/ O.lM ammonium acetate gradient buffer (20/80 to 60/40) was purified as an eluent and lyophilized to give a 3% yield (丨8 mg) of the title compound. NMR (400 MHz): 0.65-0.85 (m, 12H), 0.95-1.2 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H), 1.55-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.1 ( s, 3H), 3.95 (brs, 2H), 4.3 (d, 1H), 4.6 (ABq, 2H), 5.65 (s, 1H), 6.6 (s, 1H), 7.05 (t, 1H), 7.2 (d , 2H), 7.25-7.4 (m, 6H), 7.5 (d, 2H); • 82- This paper size applies to the Chinese National Standard (CNS) A4 specification (210X297 public Γ 1331143

m/z : 739 β Example 16 LJ_-Dioxo-5_phenyl_7-methylthiopurine_8.rN {(RU&quot; _"Ν_ LLS)-imylbutyl)aminocarbazinyl 1芊 吆 吆 醯 醯 借 借 借 借 借 借 借 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例 实例Carboxybenzyl guanylaminomethylmercapto methoxy bromide, sulphate, tetrahydro-1,2,5-benzo &lt;» dextromethine (example 25; 50 mg, 0.078 mmol) and (L) The title compound was synthesized starting from the third ester of leucine (21 mg, 〇〇95 mmol). DMF was removed and 20 ml of Et0Ac was added and washed with NaHC〇3 (51⁄4, 10 ml), 〇_1M KHS〇4 (15 ml) and saline, dehydrated and traced. The residue obtained was purified by the above flash chromatography. Confirm the title compound intermediate tert-butyl ester; m/z: 826 (M+ 1 8 (NH4+)). Purification and purification by preparative HPLC gave 21% yield (12 mg) of title compound. NMR_ (400 MHz): 0.7 (dd, 6H), 0.75-0.85 (m, 6H), 0.95-1.2 (m, 6H), 1.25-1.7 (m, 9H), 2.1 (s, 3H), 3.95 (brs , 2H), 4.3-4.4 (m, 1H), 4.6 (ABq, 2H), 5.55 (s, 1H), 6.6 (s, 1H), 7.05 (t, 1H), 7.2 (d, 2H), 7.25- 7.4 (m, 6H), 7·5 (d, 2H) ; m/z : 753. Example 17 1,1-dioxo-3,3·dibutyl-5-styl-7-indolethio-8-(Ν-(Π^_α__N. (1-(S)- L-Carboxy-2-(S)-2-methylbutyl)aminocarbazinyl 1 芊 丄 丄 醯 醯 ) ) ) ) ) ) -2 2,3,4,5-tetrazol-1,2 ,5-笨和·»塞二吖庚 by the procedure of Example 15 from 1,1-dioxo-3,3-dibutyl-5-phenyl·7-methylthio-8-[N- ((R)-α-carboxyindenyl)aminomercaptomethoxy]·2,3,4,5-tetra-83- This paper scale applies to Chinese National Standard (CNS) Α4 specification (210X 297 mm) 1331143 A7 — -______B7 V. INSTRUCTIONS (μ) Hydrogen·1,2,5-stupid and indomethacin (Example 25; 5〇mg, 〇〇78mmol) and (L)-Different White The title compound was synthesized starting from tributyl sulphate (21 mg, 0.095 mmol). DMF was added and 20 mL EtOAc was added and NaHC03 (5°/.' 10 mL), 0 1M KHS 〇4 (15 ml) After washing with brine, dehydration and concentration were carried out without purification by flash chromatography. The title compound was obtained as the titled butyl ester; m/z: 8 〇9. Yield (22 mg) of the title compound. NMR (400 MHz) 0.65-1.4 (m, 22H), 1.4-1.5 (m, 2H), 1.5-1.7 (m, 2H), 1.75-1.85 (m, 1H), 2.1 (s, 3H), 3.95 (brs , 2H), 4.25 (d, 1H), 4.6 (ABq, 2H), 5.6 (s, 1H), 6.6 (s, 1H), 7.05 (t, 1H), 7.2 (d, 2H), 7.25-7.4 ( m, 6H), 7.45 (d, 2H); m/z : 753 0 Example 1 8 . IJ—· Dioxo-3,3-dibutyl-5-phenyl-7-sulfonylthio-84N- ((R)-a-carboxyl: i-dibenzylidene)aminopurinyloxyl-1,3-,4,5-tetrahydro-1,2,5-stupidyl ,1-dioxo-3,3-dibutyl-5-phenyl-7-indolethio-8-carboxydecyloxy-2,3,4,5:tetrahydro-1,2,5- Benzothiazepine (Method 3; 295 mg, 0.58 mmol) dissolved in 10 mL DCM » sequentially added 4-(l-(R)-t-butoxycarbonyl-1-aminoindenyl) Phenol (Method 7: 160 mg, 0.72 mmol), 2,6-dimercaptopyridine (M0 μL, 1.20 mmol) and TBTU (230 mg, 0.72 mmol). The mixture was stirred for 3 hours. Additional 4-(l-(R)-t-butoxycarbonyl-1-aminoindolyl)-phenol (10 mg, 0.04 mmol) was added and mixing was continued for 2 hours. Add DCM (20 ml) and the solution is washed with NaHC03 (5%, 20 ml), KHS04 (0.3M; 20 ml) and brine (20 ml), dehydrated and concentrated to -84 - This paper size is applicable to Chinese national standards. (CNS) A4 size (210 X 297 mm) 1331143 A7 __B7 V. Description of invention (82) Volume of 10 ml. The intermediate compound of the title compound was identified as the third butyl ester; m/Z: 729 (^!+18 (&gt;^4+)). Add butyl (1.3 ml) and stir the mixture for 4.5 hours. The crude product was purified by preparative HPLC using C8 column (50 X 500 mm) and MeCN/O.lM ammonium acetate gradient buffer (40/60 to 70/30 for 40 minutes) as a solution, and lyophilized to obtain 77.5% yield. Rate (302 mg) of the title compound. NMR (400 MHz) 0.8 (t, 6H), 1.0-1.2 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H), 1.55-1.7 (m, 2H), 2.1 ( s, 3H), 3.95 (brs, 2H), 4.6 (ABq, 2H), 5.3 (s, 1H), 6.6 (s, 1H), 6.75 (d, 2H), 7.05 (t, 1H), 7.15-7.4 (m, 7H) ; m/z : 673 (M+18 (NH4+)). Example 19 hi-dioxo-3,3-dibutyl-5. phenyl-7-indolethio-8-(N-ΠΙΟ-α-ΓΝ-Li; S)-l-carboxy-4-amine Alkyl butyl) amino fluorenyl 1 fluorenyl hydrazino hydrazino)-2,3,4,5-tetrahydro-1.2.5-mosa π dioxin U-diox 3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R)-α _ {N-[(S)-1-(t-butoxycarbonyl)) -4-(oximeoxycarbonylamino)butyl]aminomethylindenyl}hydrazino)aminoindenyloxy]·2,3,4,5-tetrahydro-1,2,5- stupid The hydrazine dioxime (method 8; 0.006 mg) was dissolved in EtOAc (EtOAc)EtOAc. The DCM and TFA and residue were removed under reduced pressure for preparative HPLC purification using MeCN/NH4+ buffer 50/50 as a solution. The acetonitrile was evaporated and lyophilized to give the title compound (37%). 111^: 754.4 and 752_4 (1^-:«)_. Example 20. -1-.,I--oxo-3,3-dibutyl-5-styl-7-indolethio-8-"1^-((~1〇-〇;-{1 \1-LiS)-l-翔疾-4_(Benzyloxycarbonylamino group, butyl 1 amine fluorenyl group) section, 胗______-85- This paper scale is suitable for gg standard (CNS) ΜSpecification (21GX297 public) --- 1331143 A7 ------ B7 V. Description of invention (83) Base·〒^基1AAI: 2,3,4,5-four arrows_1.2.5-装#€二吖geng due to 1,1-dioxo-3,3-dibutyl-5-styl-7-methylthio-8-[1^-((尺)-^:-{N-[(S -l-(t-butoxycarbonyl) 4 (nonyloxycarbonylamino)butyl]aminocarbamimidyl}nonyl)aminocarbamidomethoxy]_23,4,5 tetrahydro-indole, 2,5-benzothiazetoin (method 8; 〇〇〇6 mg) was dissolved in DCM (0.1 mL), TFA (0·15 ml) was added and the mixture was stirred at room temperature for hr. The title compound was purified by evaporation of acetonitrile and lyophilized to give 35% yield (2 mg) of the title compound: /2:888.7 and 88. ]^-1^·. Example 21 Dibutyl-5-phenyl·7-methylthio-8-(Nr(R)-α-pyridin-1-ylindole, fluorenyl 1甲甲醯基甲甲基卜2.3.4.5- Tetraoxy-1 2,5-benzopyrene 2 p丫豳田1, dioxo-3,3-dibutyl-5-phenyl-7 -Methylthio-8-(N-{(R)-α-[(S)-2-(t-butoxycarbonyl)pyrrolidinylcarbonyl]benzyl)aminopurinylmethoxy)- 2,3,4,5-tetrahydro-1,2,5-benzopyrimidine (method 10; 41 mg '0.052 mmol) dissolved in DCM:TFA 4: 1 (3 mL) and stirred The reaction mixture was evaporated under reduced pressure <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> <RTIgt; Compound. M/z 737.3034. Example 22 iJ·: dioxo~-3,3-dibutyl-5-phenyl-7-carbamyl α-ΓΝ-)-N-decylaminocarboxamyl 1芊基}Neck a methyl carbyl methyl group 2.3.4.5- tetrahydro-1,2.5-benzene #4 bismuth-86- 1331143 A7 B7 V. Description of invention (84) From 1,1-diox Generation-3,3-butyl-5-styl-7-nonylthio_8-(N-{(R)-o:-[N-(second butyl thiol thiol)-N-曱 胺 胺 ] ] 节 } } } } } } } } } } } } } } } } } } } -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 Method Shushu) The method of Example 21, by the title compound was synthesized. NMR (500 MHz, 2 geometric isomers 3:1 mixture). Major stereoisomers: 〇.8(61^,6{^), 1.0_ 1.24 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.51 (m, 2H), 1.56-1.68 (m, 2H), 2.09 (s, 3H), 3.0 (s, 3H), 3.75-4.21 (m, 4H), 4.60 (ABq, 2H) , 6.01 (s, 1H), 6.58 (s, 1H), 7.05 (t, 1H), 7.16-7.28 (m, 3H), 7.3-7.45 (m, 5H), 7_48 (brd, 2H) secondary stereo The other peaks of the construct are at 2.14 (s), 3.0 (s), 4.56 (Abq), 5.81 (s), 6.61 (brs); m/z 711.4. Example 23 1,1-dioxo-3,3-dibutyl-5-styl-7-methylthio-8-(1&lt;[-~[(1〇-〇;-1~1^-) (1 - ( R) -1- retino-1-ylpropan-2-yl)amine aryl 1 宇 丨 基 基 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 -2 1.2.5-芏 嚓 吖 吖 因 1 from 1,1-·-oxo-3,3 -butyl-5-phenyl-7-methylindenyl-8-[^^-((1^ )-£^-{N-[1-(R)- 2-( R)-1-(Tertixobutoxy)-1-ylpropan-2-yl]aminomethylindenyl} fluorenyl Amino-based methoxy]-2,3,4,5-tetrahydro-1,2,5- benzopyrazine (Method 12) The title compound was synthesized by the method of Example 21. m/ z 741.3. Example 24 1,1·di- gaso-3,3-dibutyl-5-styl-7-formamyl-8-(N-URb π-“M-(sulfomethyl) Amino-based fluorenyl 1 fluorenyl)aminomethylmercaptomethyl chlorohydrazine H 4^-tetrahydro-1.2.5-mosa#»塞二吖因因铵磅_ _87- This paper scale applies to Chinese national standards (CNS) A4 size (210X 297 mm) 1331143 A7 _______B7 V. Description of invention (85) 1,1-Oxo-3,3-dibutyl-5-styl-7-methylthio-8- [1^-((11)-〇:- 叛 芊 ))) Aminocarbonylcarbonyl]-2,3,4,5-tetrahydro-1,2,5-stupid Geng (example 25; 50 mg, 0.078 mmol), aminomethanesulfonic acid (15 mg '0.088 mmol) and N-methylmorpholine (17.2 μl, 0·156 mmol) are soluble. DMF (2 ml). Add tetrabutylammonium hydrogen sulfate (35 mg, 0.103 mmol) and heat the mixture at 60 ° C for 15 minutes. Remove TBTU (45 mg ' 0 · 14 mmol) after removal. The reaction mixture was stirred at room temperature for 4 minutes and then at 60 ° C for 1 hour. After stirring overnight, 3 5 mg of TBTU was added. After 6 hours, 29 mg of TBTU was added in small portions and the mixture was stirred overnight. The product was purified using preparative HPLC using EtOAc / EtOAc (EtOAc) (EtOAc) ), 0.97-1.22 (m, 6H), 1.24-1.48 (m, 4H), 1.51-1.68 (m, 2H), 2.08 (s, 3H), 3.7-4.18 (m, 2H), 4.24 (d, 1H) ), 4.39 (d, 1H), 4.62 (ABq, 2H), 5.62 (s, 1H), 6.58 (brs, 1H), 7.02 (brt, 1H), 7.14-7.23 (m, 2H), 7.24-7.36 ( m, 6H), 7.45 (d, 2H) ; m/z: 732.9. Example 25 1,1-Dioxo-3,3-dibutyl-5-molyl-7-methylthio-8-indole-((ΙΟ·α-铋)-ylamino) Gas-based 1-2.3,4,5-tetrahydro-1.2.5- benzopyrimidine 1,1-dioxo-3,3-dibutyl-5-phenyl-7-sulfonylthio- 8-{N-[(R) - α -(Tertidinoxycarbonyl)benzyl]aminoindolyloxy]_2,3,4,5-tetrahydro-1,2,5-stupid Pyrimidine (method 9; 762 mg, 1.09 mmol) was dissolved in a mixture of TFA (6.65 mL) and triethyldecane (0.350 mL). Anti--88- This paper scale was used in Chinese national standards. (CNS) Α4 specification (210X297 public) 1331143 A7 ____B7 V. Inventive Note (86) ~~ The mixture should be stirred under reduced pressure to give the quantitative compound (714 mg). ) : 0.8 (brt,6H),0.96-1.25 (m, 6H), 1.25-1.4 (m, 2H), 1.42-1.51 (m, 2H), 1.57-1.69 (m, 2H), 2.11 (s, 3H ), 3.8-4.15 (m, 2H), 4.66 (ABq, 2H), 5.49-5.53 (m, 1H), 6.61 (s, 1H), 7.06 (t, 1H), 7.18-7.26 (m, 2H), 7.28-7.45 (m, 8H), 8.35 (d, NH); m/z 640.2. Example 26. 匕1-dioxo-3,3-dibutyl-5-stupyl-7-oxime -8-(&gt;1-{(尺)-〇;,-"1^-CIS)-1-carboxy-2-anthracene-hydroxypropyl)aminomethylindenyl iota_m·曱醯 曱醯 曱 、,-2,3·4,5-tetrahydro-1,2.5-indolopyrimidine bismuth-dioxo-3,3-dibutyl-5-phenyl- 7-Methylthio-8-[N-((R)-α-carboxy-4-hydroxybenzyl)aminoindolyloxy]_2,3,4,5_tetrahydro_U2,5_ Stupid and pyrimidine (example 1 8 ; 100 mg, 〇. 152 mmol) dissolved in 3 ml of DMF. Add o-tert-butyl-(L)-threonate tert-butyl ester (5 〇) Mg, 0.2 16 mmol, and N-decylmorpholine (34 μL, 0.309 mmol) and the mixture was stirred for 5 minutes. Add TBTU (60 mg, 0.187 mmol) and stir for 30 minutes. Add 曱The acid (1-2 drops) and the mixture were extracted with EtOAc EtOAc. The intermediate compound of the title compound was identified as the third butyl ester; m/z 869. Add DCM (3 mL) and TF A (0.5 mL) and stir the solution overnight. The mixture was concentrated and purified by preparative HPLC on a C8 column (50 X 250 mm). MeCN/0.1 M acetic acid gradient buffer (20/80 to 50/50) was used as the eluent. The title compound was obtained by lyophilization in 61% yield (71 mg). NMR (400 MHz) 0.78 (t, 6H), 0.93 (d, 3H), 1.0-1.22 (m, 6H), -89 - This paper size applies to the Chinese National Standard (CNS) A4 specification (210 x 297 mm) 1331143 A7 ____B7 V. INSTRUCTIONS (87) 1.25-1.4 (m, 2H), 1.4-1.52 (m, 2H), 1.55-1.7 (m, 2H), 2.1 (s, 3H), 3.95 (brs, 2H) ), 4.18-4.25 (m, 1H), 4.35 (d, 1H), 4.63 (ABq, 2H), 5.53 (s, 1H), 6.57 (s, 1H), 6.75 (d, 2H), 7.03 (t, 1H), 7.2 (d5 2H), 7.23-7.37 (m, 5H) ; m/z : 757. Camp 27 Oxo-3,3·monobutyl-5·phenyl·? -methyl ketone-oxime _ ((S) bis-1 thiol-2-methylpropyl)aminomethyl fluorenyl] sulfhydryl yl) amine a methoxyl)-2,3,4.5 - four Hydrogen-1,2,5-stupid and dioxin due to the procedure described in Example 26 from l,l-dioxo-3,3-dibutyl-5-phenyl-7-methylthio- 8-[N-((R)-α-carboxy-4-hydroxybenzyl)aminoindolyloxy]_ 2,3,4,5-tetrahydro-1,2,5-benzopyrimidine Dioxeine (Example 18; 7 mg, 〇1 〇 8 mmol) and (L)-tridecyl valine (31 mg, 〇148 mmol) were used to synthesize the title compound. Confirm the intermediate compound of the title compound, tert-butyl ester; m/ ζ 811. Hydrolysis and purification by preparative HPLC gave 56 mg (yield: 69%) of title compound. NMR (400 MHz) 0·7-0_75 (m, 16H), 0.79 (t, 6H), 0·96-1.24 (m, 6H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H) ), 1.54-1.7 (m, 2H), 2.0-2.2 (m, 1H), 2.1 (s, 3H), 3.95 (brs, 2H), 4.22 (d, 1H), 4.6 (ABq, 2H), 5.54 ( s, 1H), 6.58 (s, 1H), 6.75 (d, 2H), 7.03 (t, 1H), 7.2 (d, 2H), 7.23-7.37 (m, 5H); m/z: 755. Example 28 1,1-dioxo-3,3-dibutyl_5_moseta-7-methylthio-8-(N-UR)-α Να S)-l-carboxybutyl) Amine醯 1-4-hydroxymercaptoamine 篡曱醯 a certain methoxy)-2,3,4,5-tetrahydro-1.2.5-mometin dioxime by the procedure of Example 26 from ι , ΐ-dioxo-3,3-dibutyl-5-phenyl-7-methyl ____-90- This paper scale applies to China National Standard (CNS) A4 specification (210X297 public) 1331143 A7 B7 five ,Inventive Note (Ming) Mercapto-8-[N-((R)_α-carboxy-4-hydroxyindenyl)aminoindolyloxy]-2,3,4,5-tetrahydro- Us·Stupid pyrimidine (Example 18; 36 mg, 0.054 mmol) and (L)-n-decylamine tert-butyl ester hydrochloride (16 mg, 0.076 mmol) starting synthesis title Compound. The intermediate compound of the title compound was identified as the third succinic acid; m/z. NMR (400 MHz) 0.7-0.85 (m, 9H), 0-97-1.22 (m, 8H), 1.25-1.4 (m, 2H), 1.4-1.5 (m, 2H), 1.5-1.8 (m, 4H) ), 2.1 (S, 3H), 3.95 (brs, 2H), 4.27 (dd, 1H), 4.6 (ABq, 2H); 5.45 (s5 1H), 6.58 (s, 1H), 6.75 (d, 2H), 7.03 (t, 1H), 7.19 (d, 2H), 7.23- 7-37 (m, 5H) ; m/z : 755. Example 29 Ge-3,3-dibutyl-5-phenyl-7-indolyl-8-(yi{(1〇-〇:-"1^-ylpropyl)aminocarbamyl 1- 4-hydroxyl-mercaptoaminoguanidinomethyl-l-yl)-2,3,4,5-tetrahong-1,2,5-stupid and quinone dioxime broadly due to M_dioxo-3,3 -Dibutyl-5-styl-7-methylthio-8-[N-((R)-a-carboxy-4-ylhydrazino)aminocarbenylmethoxy]_2,3, 4,5_tetrahydro+2,% benzo-11 stopper dioxime (Example 18; 0.075 g, 0.114 mmol), butyric acid 2-amino-1,1-dimethylethyl hydrochloride A solution of the salt (2S)-(0.031 g, 0.160 mmol) and N. decylmorpholine (0.050 mL, 0.457 mmol) in DMF (4 mL) was stirred at RT for 10 min then TBTU (0· (Μ8g, 〇"49mmol). After 1 hour, the ester was completely converted. Μ/ζ: 797.4. The solution was diluted with toluene and concentrated. The residue was dissolved in DCM (5 mL) and TFA (2 mL) The mixture was stirred for 7 hours. The solvent was removed under reduced pressure. The residue was purified by preparative HPLC using 20-60% MeCN in 〇·Ι Μ ammonium acetate gradient buffer.

1331143 A7 _B7 V. INSTRUCTIONS (89) Purification by chaotropic solution. The title compound was obtained as a white solid. NMR (400 MHz, DMSO-d6): 0.70 (3H, t), 0.70-0.80 (6H, m), 0.85-1.75 (14H, m), 2.10 (3H, s), 3.80 (2H, brs), 4.00 -4.15 (1H, m), 4.65 (1H, d(AB)), 4.70 (1H, d(AB)), 5.50 (1H, d), 6.60 (1H, s), 6.65-7.40 (11H, m) , 8.35 (lH, d), 8.50 (1H, d), 9.40 (1H, brs) » Example 30 1.1-Dioxo-3,3-dibutyl-5-benyl-7-methylthio--8 -(N-{( R) - j - "Να R)-l-carboxy-2-sulfonylethyl)aminoguanidino 1 -4-hydroxyindole fluorenyl fluorenylmethyl )-2,3,4,5-tetrahydro-1,2,5-stupid, stilbene 1,1-di-lacto-3,3-·-butyl-5-benyl-7 - thiol- 8-[N-(( R ) - α - idyl-4-hydroxyindolyl)aminomethylindolyloxy]-2,3,4,5-tetrahydro-1,2 , 5-phenylpyrazine (Example 18; 0.075 g, 0.114 mmol), S-decyl-L-cysteine tert-butyl ester (Pestic. Sci.; ΕΝ; 45; 4; 1995; 357_362; .0.031 g, 0.160 mmol) and a solution of N-methylmorphine (0.050 ml, 0.457 mmol) in DMF (4 ml) at RT for 10 min, then TBTU (0.048 g) , 0.149 millimoles). After 1 hour, the conversion is complete M/z: 829.5. The reaction mixture was diluted with decanoic acid (15 mL) and was stirred for 17 hours at 5 ° C. The solution was diluted with benzene and then concentrated. The residue was purified by preparative HPLC using 20-60% MeCN /O.lM ammonium acetate gradient buffer was purified as a solvent to give the title compound: EtOAc (EtOAc: EtOAc: EtOAc: 12H, m), 1.85 (3H, s), 2.10 (3H, s), 2.60-2.80 (2H, m), 3.85 (2H, brs), 4.15-4.30 (1H, m), 4.65 (1H, d( AB)), 4.70 (1H, d(AB)), 5.50 (1H, d), 6.60 (1H, s), 6.60-7.35 (11H, m), 8.30 (1H, d), 8.40 (1H, d) , 9.40 (1H, brs). -92- This paper size is applicable to China National Standard (CNS) A4 specification (210x 297 mm) 1331143 A7 B7 V. Invention description (9〇) Example 3 1 1,1-~-Milk-3,3 -2 Butyl-5-phenyl-7-thiol-""Ν-ί^ 曱 ) ) ) ) ) ) 胺 胺 胺 1 1 1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 -1 , 2,5-benzodiazepine U-dioxo-3,3-dibutyl-5-phenyl-7-methyl-8-carboxymethoxy-2.3.4.5-tetrahydro-1, 2,5-stupid and indomethacin (method 5; 0.050 g, 0.105 mmol), (R)-a -[Ν-(t-butoxycarbonylindenyl)aminoindolyl] amide (Method 86 of WO 02/50051; 0.039 g, 0.148 mmol) and N-.methylmethine (0.046 ml '0.417 mmol) of 0匚14 (4 ml) dissolved in 1 Mix for 20 minutes, then add TBTU (0.044 g, 0.137 mmol). After j, then complete the conversion to ester (m / z: 721.2 (M + 1) +). Remove the solvent and residue in a vacuum. Citrate (5 ml). The reaction was stirred for 17 hours and then concentrated. The residue was purified by preparative HPLC using 40-60% MeCN / O. The title compound 〇, 〇 44 g (63%). NMR (400 MHz, DMSO-d6): 0.65-0.80 (6H, m), 〇·85_ 1.60 (12 Η, m), 2.10 (3H, s), 3.40-3.65 (2H, m), 3.70 (2H, bs), 4.60 (1H, d(AB)), 4.70 (1H, d(AB)), 5.55 (1H, d), 6.70 (1H, s), 6.80-7.50 (12H, m), 8.20-8.30 (1H, m), 8.55 (1H, d). Example 32 1,1_------, 3-dibutyl-5-benyl-7-methylsulfide Base (R) - α - "n_ LLS_)-1-carboxypropyl)aminomethylmercapto 4-hydroxyindole amine oxy-yl)-2,3.4,5-fourfi.-1.2.5 -Benzene·&gt;Sedanoxin 1,1-dioxo-3,3-dibutyl-5-phenyl-7-mercapto-8-carboxymethoxy·2.3.4.5- Tetrahydrogen -l,2,5-benzopyrimidine (method 16; 〇_〇5 gram, -93- This paper scale applies to Chinese National Standard (CNS) A4 specification (210 X 297 mm) 1331143 A7 B7 V. INSTRUCTIONS (91) 0.105 mmol/(R)_α 3rd butoxycarbonyl)propyl]aminoglycolyl}-4-hydroxybenzylamine (Method 19; 〇〇45 g, 〇 .146 mmoles and a solution of N-methylmorpholine (0.047 ml, 0.427 mmol) in DCM (4 mL) stirred at RT for 15 min. ΤΒτυ (〇·〇44g, 0.137 mmol). After 17 hours, the conversion to the ester was completed (m/z 765·7 (Μ+ 1) + ). The solvent was removed under reduced pressure and the residue was dissolved in EtOAc (5 mL). The solution was stirred for 3 days and then concentrated. EtOAc EtOAc m. NMR (400 MHz, DMSO) 0.60 (3H, t), 0. 65 - 0. 80 (6H, m), 0.85-1.75 (14H, m), 2.10 (3H, s), 3.75 (2H, bs), 3.90-4.05 (1H, m), 4.60 (1H, d(AB)), 4.65 (1H, d(AB)), 5.50 (1H, d), 6.65-7.30 (11H, m), 8.15 (1H, d ), 8.40 (1H, d). Example 33 1, dioxo-3,3-dibutyl hydrazine _styl _7_ fluorenyl fR)- α -ΓΝ-L(S)-l-"N-((S)-2- Hydroxy-indole carboxyethyl)amino hydrazide 1 yl}amino fluorenyl 1 fluorenyl}aminomethylhydrazine a methyl group) 2,3,4.5-tetra'-丨.2.5-benzo Pyrimidine due to 1,1-dioxo-3,3-dibutyl-5-styl-7-mercapto-8-(1\[-{(11)-&lt;3!- [ N-((S)-1-{N-[(S)_2-(T-butoxy)-1-(t-butyl.oxycarbonyl)ethyl]aminocarbamoyl}propyl)amino Indenyl]benzyl}aminomethylindolyloxy)·2,3,4,5-tetrahydro-1,2,5-stuppy p-dioxine (Method 20; 14 mg, 0.015 Milliol) in a mixture of DCM: TFA (3:1, 4 ml). The reaction mixture was stirred for 3.5 hours. The solvent was evaporated under reduced pressure. The product was used as a preparative hpl C. Liquid (5/95 to 10 〇 / 〇) as a solution pure -94- This paper scale applies to China National Standard (CNS) A4 specification (210X297 mm)

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Line 1331143 A7 ____B7 V. Description of the invention (92), the title compound was obtained, 8 mg (65o/o). NMR (400 MHz): 0·70-0.83 (m, 9H), 0.9-1.40 (m, 8H), 1.40-1.52 (m, 2H), 1.52-1.70 (m, 3H), 1.77-1.88 (m, 1H), 2.11 (s, 3H), 3.8-4.1 (m, 4H), 4.29 (dd, 1H), 4.37 (t, 1H), 4.63 (ABq, 2H), 5.57 (s, 1H), 6.60 (s , 1H), 7.04 (brt, 1H), 7.20 (brd, 2H), 7.25-7.40 (m, 6H), 7.47 (d, 2H); m/z 812.3. Example 3 4 _1,1-dioxo-3,3-dibutyridin-5-methyl-7-methylthio-8-(Ν·( (R) - α -Γ2-(S)-2- (carboxy)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl 1 year. 胺.amine a certain methyl methoxy)-2,3,4.5-tetradec-1,2 ,5-benzox»sedoxime 1,1-dioxo-3,3-dibutyl-5-phenyl-7-indolylthio-8-(]^-{(11)- (2-[2-(S)-2-(methoxycarbonyl)-4-(R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}aminocarboxamidineoxy)- 2,3,4,5-tetrahydro-1,2,5-benzoxanindole (Method 21; 23 mg '0.030 mmol) dissolved in THF: Η20 mixture (1:1 ' 1 Add argon arsenide (monohydrate, 2 mg, 0.048 mmol) and stir the mixture for 2 hours. Leave 50% starting material so add other hydroxide chains (3 mg) and stand for 1 hour. The reaction was not complete, so the addition of hydrogen peroxide (2 mg) and the reaction was stirred overnight. The product was used as a preparative ^^1^ using 1^0^/0_1] ammonium acetate gradient buffer (5/95 to 1 〇). 〇/〇) Purified as a solution to give the title compound, 12 mg (53%). Μ/ζ 753.04 ° Example 3 5 1 &lt; 1 ~ monooxo-3 3-butyl-5-benyl-7-sulfonyl--f2-(S)-2-(suppressed) succinyl-1-yl-l-yl 1 decyl fluorenyl methoxyl Base)_ 2,3.4,5-tetrahydro-1,2.5-mosa #pyroxypyrene-95- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1331143 A7 _____B7__ V. Invention Description (93) 1,1-dioxo-3,3-dibutyl-5-styl-7-methylthio_8-(1^-{(11)-«-[2-(S) -2-(Tertidinoxycarbonyl)azetidine_丨-ylcarbonyl]:yl}aminomethylmercaptomethoxy)-2,3,4,5-tetrahydro_ι,2,5- Stupid and 11 dioxin (method 22; 27.5 mg, 0.035 mmol) dissolved in DCM (3 mL) and tfa (1 mL). The reaction was stirred for 1.5 hr. Obtained 25 mg of title compound. Μ / z 722.92. Example 36 1,1-dioxo"^-3,3-dibutyl-5-芏篡-7. Jiayi _8_(^-((1 〇-0:.-"1^-{(S)_-丨N:Hg.)__-l·carboxyethyl)amine 篡A 醯1 B ' 'aminomethyl hydrazine 】 benzyl guanamine shy ^甲醯基曱气)-2,3,4.5-四^ -1.2.5·Benzene 嚓2吖0_ 1,1 oxo_3,3_ butyl-5-stupyl-7-曱Thio-8-(1^-{(1^)-(2!-[N-((S )-l-{N-[(S)-l-(Tertidinoxycarbonyl)ethyl]aminoindenyl}ethyl)aminomethylindenyl]benzyl}aminoindenyloxy -2,3,4,5-tetrahydro-1,2,5-benzopyrimidine (Method 26; 34 mg, 0.041 mmol) dissolved in DCM: mixture of TF A (3:1) , 4 ml). The reaction mixture was stirred for 2 hours. The solvent was distilled off under reduced pressure. The product was purified by preparative HPLC using EtOAc EtOAc EtOAc (EtOAc) NMR (500 MHz, CD3OD) 0.81 (bt, 6H), 0.88-1.54 (m, 16H), 1.56-1.71 (m, 2H), 2.11 (s, 3H), 3.8-4.2 (m, 2H), 4.33- 4.42 (m , 2H), 4.66 (ABq, 2H), 5.55 (s, 1H), 6.61 (s, 1H), 7.〇7 (t, 1H), 7.22 (brd, 2H), 7.28-7.43 (m , 6H), 7.48 (d, 2H) ; m/z 782. Example 3 7 -96- The paper music scale applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

Binding

Line 1341143 A7 ____ B7 _ V. Description of invention (94) Gaso-3.3-dibutyl-5-methyl-7-indole sulfur-KN-Uip-α-"N-carboxy-3.3-dimethylbutyl Aminomethyl hydrazine, a hydrazinyloxy group, -2.3.4.5-tetrahydro-1,2.5-molecule, and diterpene; and L·!·-diode -3Ί3-dibutyl-5-phenyl-7-nonylthio-8-(Ni(R)-α-ΓΝ-LLiM-铋-3.3-dimethylbutyl)aminocarbyl Amino 曱醯 • . 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 1, 1, 1, 1, 1, 1, 1, 1, Phenyl-7-fluorenyl-8-[N-((R)-carboxycarbyl)aminomercaptomethoxy]-2,3,4,5-tetrahydro-1,2,5 -Benzazepine dioxime (Example 25; 51 mg, 0.080 mmol) dissolved in 2 mL of DMF. Add 4-mercapto D, L-leucine tert-butyl ester (Method 27; 23 mg) , 〇.114 mmol, N-mercaptomorpholine (18 μl, 0·163 mmol) and TBTU (31 mg '0.097 mmol) and the mixture was stirred for 2 hours. Add 1 drop of citric acid and The mixture was extracted with EtOAc and EtOAc (EtOAc)EtOAc. After dehydration with Na.sub.2SO.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.sub.ssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssssss Purified on a C8 column (50×250 mm). MeCN (20-50%) in 0.1 M ammonium acetate gradient buffer was used as the eluent. Under these conditions, the two diastereomers were separated and separately collected. Freeze-drying. The first dissociation of the diastereomers gave 5 mg (16% yield) and the second dissolved diastereomer afforded 3 mg (10% yield). Absolute configuration by comparison NMR-charge The spectrum and related compounds are confirmed, and the diastereomers which are first dissolved are (R,R)-diastereomers and the diastereomers of the second dissociation are (R,S)-non-pairs. Aminos. M/z: 767. (R, R) · diastereomers nmr ____-97- This paper scale is suitable for National Standard (CNS) A4 specification (210X297 public) 1331143 A7 ____B7__ V. Description of invention (95) (400 MHz): 0.79 (t, 6H), 0.95 (s, 9H), 0.99-1.22 (m, 6H), 1.25-1.39 (m, 2H), 1.40-1.51 ( m, 2H), 1.57-1.68 (m, 3H), 1. 80 (dd, 1H), 2.08 (s, 3H), 3.95 (brs, 2H), 4.47 (dd, 1H), 4.63 (Abq, 2H), 5.61 (s, 1H), 6.58 (s, 1H), 7.04 (t, 1H), 7.20 (d, 2H), 7.25-7.35 (m, 6H), 7.43-7.47 (m, 2H) » (R,S)-Diastereomer NMR (400 MHz): ( ( ( ( ( ( ( ( , 2H), 1.76 (dd, 1H), 2.12 (s, 3H), 3.95 (brs, 2H), 4.35 (dd, 1H), 4.60 (Abq, 2H), 5.54 (s, 1H), 6.60 (s, 1H), 7;04 (t, 1H), 7.20 (d, 2H), 7.24-7.37 (m, 6H), 7.39-7.46 (m, 2H). Example 3 8 Oxo-3.3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-α-"N-carboxy-3.3-didecylbutyl)amine Methyl ketone 1-4-hydroxy hydrazine 胺 胺 胺 } 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 1-1 ,1-dioxo-3,3-dibutyl-5-phenyl-7-sulfonylthio-8-[N-((R)-a-carboxy-4-hydroxybenzyl)aminocarbamidine Preparation of the title compound by the initial preparation of the title compound. </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> </ RTI> The third butyl ester. Μ / z : 839. Purification of the preparative HpLC from the racemic title compound collected only one diastereomer. 4 mg (12%) was obtained. (R,R)_Diastereomer. m/z: 783 »NMR (400 MHz): 0.79 (t, 6H), 0.95 (s, 9H), 0.99-1.22 (m, 6H), 1.25- 1.39 (m, 2H), 1.40-1.51 (m, 2H), 1.56-1.68 (m, 3H), 1.79 (dd, 1H), 2.08 (s, 3H)&gt; 3.96 (brs, 2H), 4.47 (dd , 1H), 4.62 (Abq, 2H), 5.47 (s, 1H), 6 58 (s, 1H), 6.73 (d, 2H), 7.04 (t, 1H), 7.19 (d, 2H), 7.24-7.35 (m, household materials (CNS) A4— (21QX297 mm y-- 1331143 A7 B7 V. Inventive Note (96) 5H). Example 3 9 1^.-Dioxo-3,3-dibutyl-5-styl-7-methylindenyl- ?^&gt;^((11)-^!々LLR)-1-carboxy-2-(trimethyldecyl)ethyl 1amine|methyl hydrazide}_4_鼗鼗竽)aminocarbamidine Methoxy 1 ,2,3,4,5-tetrahydro-1.2,5-indolopyrimidine and 1^_oxo-3,3,dibutyl-5-styl-7- Sulphur -8-[]^((10-^;々^[-L(S)-l-carboxy-2-(trimethyldecyl)ethyl 1 基 醯 醯 丨 _ _ _ xiang A mercapto) amino-alkyl methoxy bromo 2,3,4.5-tetrahydro-1.2.5-stuppy p-pyrene dipyridyl 1,1 dioxo-3,3·dibutyl- 5-phenyl-7-methylthio-8-[N-((R)-α-carboxy-4-hydroxyindenyl)aminomercaptomethoxy]_2,3,4,5-tetrahydro u,5_benzoxanoxaxine (Example 18; 55 mg, 0.084 mmol) and methyl 3-(trimethyldecyl) alanate (Method 28; 19 mg, 0.108 mmol) Dissolved in 3.5 ml of DMF. N-methylmorpholine (18 μL, 163·163 mmol) and TBTU (32 mg, 0.101 mmol) were added sequentially and the mixture was stirred for 2 hours. 1 drop of formic acid and the mixture were extracted between EtOAc and water. The aqueous phase (pH = 3) was washed with EtOAc. The combined organic layers were washed with 1% NaHC solution brine and dried over NazSO4. Confirm the intermediate of the title compound, methyl vinegar. M/z: 813. Add THF (2 mL), water (2 mL) and UOH (1 mM [0.41 8 mM) and mix overnight. Preparation of the mixture

HPLC was purified on a C8 column (50 X 1 mm). A 20-50% MeCN 0. ammonium acetate gradient buffer was used as the eluent. The two diastereomers were separated under these conditions and separately collected as lyophilized 8 mg (24% yield) of the first dissociated diastereomer and 8 4 mg (25% yield). Second dissolvate. -99-

1331143

The absolute configuration is confirmed by comparing NMR-spectroscopy with related compounds to confirm that the diastereomers of the first dissociation are (R,R)-diastereomers and the second dissociation diastereomers are ( R, S) - diastereomer. M/z: 799. NMR (400 MHz) for (R,R) diastereomers: -〇_i6 (s, 9H), 0.79 (t, 6H), 0.9-1.22 (m, 8H), 1.25-1.40 (m, 2H), 1.40-1.52 (m, 2H), 1.55-1.68 (m, 2H), 2.11 (s, 3H), 3.95 (brs, 2H), 4.29-4.35 (m, 1H), 4.58 (Abq, 2H) , 5.45 (s, 1H), 6.59 (s, 1H), 6.73 (d, 2H), 7.04 (t, 1H), 7.17-7.27 (m, 5H), 7.32 (t, 2H), and (R, S ) - nmr (400 mHz) of diastereomers : 0.04 (s, 9H), 0.79 (t, 6H), 1.00-1.22 (m, 8H)S 1.25-1.40 (m, 2H), 1.40-1.52 (m, 2H), 1.55-1.68 (m, 2H), 2.08 (s, 3H), 3.95 (brs, 2H), 4.40-4.46 (m, 1H), 4.62 (Abq, 2H), 5.49 (s, 1H ), 6.58 (s, 1H), 6.73 (d, 2H), 7.04 (t, 1H), 7.14-7.36 (m, 7H) « The starting materials for the above examples are commercially available or easy to borrow Standard methods are prepared from known materials. For example, the following reactions illustrate, but are not limited to, some of the starting materials used in the above reactions. Method 1 U didioxo 2,3-dibutyl-5-stupyl^ desert·8•ethyl gas ketone group _ 2,3^4,5-tetrahydro-1,2,5- Stupid and 4 吖庵闵; ^ Oxo 3,3-dibutyl 皋 "j_· Stupid-7- formazan-8-ethylhydrocarbonyl fluorenyl-2,3,4,5-tetrahydro -1,2,5-策#1»窠二1»丫丫闵1,1-di-oxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy -2,3,4,5-tetrahydro-1,2,5-benzopyrimidine (prepared according to w〇98/381 82; 〇218 g, 5.65*104 mol) DMF (5 ml Add NaSMe -100 to the suspension. This paper scale applies to China National Standard (CNS) A4 specification (21〇X 297 public attack:) 1331143 A7 ___B7__ V. Invention description (98) (0.210 g, 2.83 mmol, 95%), and the mixture was stirred at 120 ° C for 5 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc andEtOAc. Concentrate. The residue is dissolved in MeCN (7 mL) and ethyl bromoacetate (0.063 mL, 5.65*10·4 mol), tetrabutylammonium bromide (0.018 g, 5.65*1〇-5 mol) and carbonic acid Sodium (0.250 g, 2.36 mmol). Mixture The solvent was removed and the residue was partitioned between EtOAc and EtOAc (EtOAc) elute 6: 1) The title compound is obtained as a colorless oil: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonylmethoxy-2,3,4 ,5-tetrahydro-l,2,5- stupid and indomethacin, 0·187 g (58%). NMR (400 MHz, CDC13) 0.70-0.80 (m, 6H), 0.90-1.70 (m , 15H), 3.90 (brs, 2H), 4.25 (q, 2H), 4.35 (brs, 1H), 4.65 (s, 2H), 6.95-7.40 (m, 7H); and 1,1-dioxo- 3,3-Dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonylcarbonyloxy-2,3,4,5-tetrahydro-1,2,5-benzo- as diterpene Geng, 0.024 g (8%). NMR (400 MHz, CDC13) 0.70-0.85 (m, 6H), 0.90-1.70 (m, 15H), 2.10 (s, 3H), 3.90 (brs, 2H), 4.20 (brs, 1H), 4.25 (q, 2H), 4.65 (s, 2H), 6.55 (s, 1H), 6.95-7.35 (m, 6H). Method 2 -1,Bu-Oxo-3,3-~-butyl-5-yl-7-indol-8-c-ylmethoxy-2,3.4,5-tetrahydro-1,2.5- Stupid and dioxin due to 1,1-di-oxo-3,3-dibutyl-5-phenyl-7-bromo-8-ethoxycarbonyloxyl 2,3,4, Add NaOH (0.052 -101 -) to a solution of 5-tetrahydro-1,2,5-stupidin indole (method 1; 0.184 g '3·24*10·4 mol) in EtOH (7 ml) This paper scale applies to the Chinese National Standard (CNS) A4 specification (210X 297 public 1131143 A7 ______B7 V. Invention description (&quot;) gram ' 1.30 millimoles) and the mixture is stirred overnight. The solvent and residue are removed under reduced pressure. The mixture was extracted with EtOAc and EtOAc (EtOAc)EtOAc. The title compound of the solid was 0.173 g (99%). NMR (400 MHz, * · CD3OD) 0.70-0.85 (m, 6H), 0.95-1.70 (m, 12H), 3.90 (brs, 2H), 4.50 (s, 2H) ), 6.90-7.40 (m, 7H) Method 3 1^1-dioxo-3.3-dibutyl-5-styl-7-mercapto-8-carboxyl anthracene-2,3,4 , 5- 1. -1.2.5-Bista pyrimidine is due to 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-ethoxycarbonyloxyloxy -2,3,4,5-tetrahydro-1,2,5-benzothiazepine (Method 1; 0.024 g, 4.49 M0·5 mol) in EtOH (3 mL) was added NaOH ( 0.007 g, 1.80*1 〇·4 mol), and the mixture was stirred overnight. The solvent and residue were evaporated. 〇〇 21 g (92 〇 / 〇). NMR (400 MHz, CD3OD) 0.70-0.85 (m, 6H), 1.00-1.70 (m, 12H),

2.10 (s, 3H), 3.90 (brs, 2H), 4.55 (s, 2H), 6.60 (s, 1H), 6.90-7.35 (m, 6H). Method 3A monooxo-3,3-dibutyl-5-phenyl-7-methylamido-8-rebel methyl group·2,3,4,5-tetrahydro-1,2.5-stupid违二;?丫庚因 (name one method) 1,1-dioxo-2-(4-decyloxybenzyl)-3,3-dibutyl-5-phenyl-7-decylthio -8-(Tertidinoxycarbonylmethoxy)-2,3,4,5·tetrahydro-l,2,5-benzothiazepine-102- This paper method is applicable to the application of the solid home standard ( CNS) A4 size (210X 297 mm) 1331143 A7 _________B7 V. Description of invention (100) Gyne (Method 25; 6.902 g ' 10.11 mmol) dissolved in TFA (5 〇 ml) and Et; 3 S i ( 8 Mix the solution in ML) for 9 minutes. The solvent was removed under reduced pressure and the residue was dissolved in &lt;RTI ID=0.0&gt; The organic phase was washed with water (20 mL) and then extracted three times with dilute NaOH (2×50 mL, 〇·5 。). The combined aqueous extracts were acidified with dilute HC1 (70 mL, 1 EtOAc) (pH 1-2) and then extracted twice with t-BuOMe (2 X 50 mL). The layer was washed with brine, dehydrated and concentrated with MgS 4 to obtain the desired product of 4.694 g (92%) of brown oil. NMR (400 MHz, CD3OD) 0.70-0.85 (m, 6H), 1.00-1.25 (nl, 6H), 1.25-1.50 (m, 4H), 1.55-1.70 (m, 2H), 2.10 (s, 3H), 3.90 (brs, 2H), 4.55 (s, 2H), 6.60 (s, 1H), 6.95-7.35 (m, 6H). Method 4

Lg〇-N-decyloxycarbonyl-α-ΓΝ-(Third-butyl carbonylmethyl)amine-mercapto-l-(2R)-{[(benzyloxy)carbonyl]amino}(phenyl)acetic acid (1 g, 35 mmol) and t-butylglycine hydrochloride (6.3 g, 37.4 mmol) and 2,6-lutidine (8-2 ml '70·4 mmol) ) Dissolved in DCM (200 ml). After stirring for 5 minutes at 〇 ° C, TBTU (12.4 g, 38.6 mmol) was added and stirring was continued at 〇 ° C for 1.5 hours and at room temperature for 3.75 hours. The reaction mixture was washed with EtOAc EtOAc m. NMR (500 MHz, CDC13): 1.45 (s, 9H), 3.84 (d, 1H), 4.00 (dd, 1H), 5.10 (m, 2H), 5.28 (brs, 1H), 6.13 (brs, 1H), 6.23 (brs, 1H), 7.30-7.44 (m, 10H). Method 5 _ -103- This paper scale applies to Chinese National Standard (CNS) A4 specification (210X 297 mm) 1331143 A7 ____B7 V. Inventive Note (101) (R)- α (Oxocarbonylcarbonyl) Aminoguanidine Base 1 amide (RO-N-oxycarbonyl _α _[N_(Tertidinoxycarbonyl fluorenyl) fluorenyl] amide (Method 3; 12.8 g '32.2 mmol) dissolved in EtOH ( 99%, 200 ml) and toluene (50 ml). Add pd/c (1% by weight, 〇65 g) and hydrogenate at room temperature for 5.5 hours at atmospheric pressure. The reaction mixture was filtered through celite and evaporated to give the title. Compound (8.4 g, 99%) » NMR (600 MHz, CDC13): 1.45 (s, 9H), 3.93 (m, 2H), 4.54 (s, 1H), 7.31-7.42 (m, 5H), 7.51 (brs) , 1H) » Method 6 2-{ |~(2|^_-2-Aminodiylphenyl)ethinylamino}}ethane 碏酴N-Bpc-(D)-4-hydroxyphenyl Glycine (3 g, 3 21 mmol) in DMF (5 mL) and tetrabutylammonium taurate (2 36 g, 6 42 mmol) with additional DMF (5 mL) Add. The resulting suspension was cooled on ice and added with TBTU (1.24 g, 3.85 mmol) for 30 minutes, the ice was removed and the mixture was stirred for 2 hours. After </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> <RTIgt; </ RTI> </ RTI> <RTIgt; The title compound was obtained as a white solid, 626 mg (71%). NMR (DMS 〇 _d6): 2 4 2 6 (m, 2H), 3.2-3.4 (m, 2H), 4.79 (s, 1H), 6.78 (d, 2H), 7.23 (d, 2H), 8.22 (t, 1H), 8.4 (brs, 3H), 9.7 (s, 1H) 〇 Method 7 j_-( 1-(R)_-Third Butoxide Carbonyl-丨·胗-ylformamidine) age · sulfuric acid (concentrated, 1 ml) was added to D_(R) · 4_hydroxyphenylglycine (1.0 g, 6.0 mmol) placed in Teflon@瓶14_Dioxane (8 ml) solution -104- 1331143

in. The bottle was cooled to -78 ° C and isobutylene (8 g, 142.6 mmol, condensed at -78 C) was added. The bottle was placed in a high temperature bottle at room temperature and stirred for 5 hours. The high pressure bottle is cooled on ice and opened. The excess isobutylene was evaporated and the residual solution was poured into aqueous NaOH (2M, 20 mL). The aqueous phase was slightly acidified to pH = i using 2MHC1 and extracted with EtOAc (3 x 75 mL). The organic phase was washed with brine, dehydrated and concentrated. The obtained product was recrystallized from diethyl ether / hexane. Quality: 〇 55 grams (41%). NMR (6〇〇MHz, CDC13) 1.45 (s, 9H), 4.45 (s, 1H), 6.8 (d, 2H), 7.25 (d, 2H); m/zi 224 0 Method 8 1,1-dioxo Generation-3,3-dibutylyl_7_methylamido_8_"Ν((Ιη_α "Nf(S)-l-(dioxaoxy)- 4"丄^oxycarbonylamino)butyl] A certain group of amines, a group of alkaloids, an amine group, an alkaloid group, an oxygen group, a 3,4,5_four blue _ 丨, 25 _ 舁 舁 4 吖庵 1 1, 1, 1- oxo-3,3 -dibutyl-5-phenyl_7_ sulfoximine_8_[Ν·((Κ)_ α carboxybenzyl)aminomethylmercapto oxime 2,3,4,5_tetrahydro_1 , 2,5-benzothiazepine (Example 25; 53 mg, 〇.083 mmol), π·[(decyloxy)carbonyl]-L-ornithine tert-butyl ester (35 mg , 〇〇98 mmol, Ν·曱 吗 morpholine (0.027 ml) was placed in DCM (5 mL). The mixture was stirred at room temperature for 〇 min, then TBTU (32 mg, 〇1 〇m) was added and the reaction mixture was stirred 1.5 min 4 EtOAc. Purification as a solution gave the title compound 57 mg (72%). Μ/ζ=944·7 and 942.7 (M-Η). Method 9 -105- This paper scale applies to China National Standard (CNS) Α4 specification (210X 297 Gonglong·) 1331143 A7 ____B7 V. Invention description (1〇3) 1^1.-dioxo-3,3- Dibutyl-5-styl-7-decylthio-8-{&gt;1-"(1〇-0:-(Tertiary oxycarbonyl)benzyl 1amino-indenylmethoxy oxime- 2.3.4,5-tetrahydro-1.2.5-.benzene-indoloquinone due to 1,1-dioxo-3,3-dibutyl-5-phenyl-7-sulfonylthio-8 -carboxyloxy-2,3,4,5-tetrahydro-1,2,5-benzoxanthene (Method 3; 627 mg, 1.24 mmol) in DCM (25 mL) Add (2R)-amino (p-styl) acetic acid tert-butyl ester (308 mg, 1.48 mmol), 2,6-di-f-pyridine (288 μl, 2.47 mmol) and TBTU (477 mg, 1.48 mmol. The mixture was stirred for 3.5 hours. The reaction mixture was reduced in vacuo. The product was purified using EtOAc EtOAc EtOAc EtOAc (EtOAc) Approximately 694 mg of pure compound was collected. The other fraction was purified a second time using an Isolute column (10 g, silica gel). The product was taken using DCM: EtOAc, 100:0, 95:5 90: 10 Gradient gradient elution. The pure fraction was added to the first fraction to give 787 mg (9 1%) of the title compound. NMR (400 MHz, CDC13) 0.78 (t, 6H), 0.92-1.12 (m, 4H), 1.12-1.46 (m, 6H), 1.54 (s, 9H), 1.58-1.72 (m, 2H), 2.14 (s, 3H), 3.8-4.05 (m, 2H), 4.32 (brs, NH) , 4.56 (ABq, 2H), 5.56 (d, 1H), 6.56 (s, 1H), 7.04 (t, 1H), 7.10 (brd, 2H), 7.24-7.42 (m, 8H), 7.84 (d, NH m/z 694.7 (MH), Method 10 1,1-di- gaso-3,3-dibutyl-5-phenylene-7-indolethio-8-(N-UR)-a · KS )-2-(笟三丁气蒺基)pyrrolidine-1-one carbonyl 芊 丨 丨 某 某 某 某 某 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 4 dioxin due to 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[N-((R) - a carboxy-106- paper scale Applicable to China National Standard (CMS) A4 specification (210 X 297 mm) 1331143 A7 ______B7___ V. Description of invention (104) hydrazinyl)aminomethylmercaptomethoxy]_2,3,4,5-tetrahydro- 1,2,5-benzoxazepine (Example 25; 50 mg, 0.078 mmol) and L-proline tert-butyl ester (15 mg, 0.088 mmol) in DCM (2 mL) Yue and N- methylmorpholine was added (17.2 [mu] L '0.156 mmol) and TBTU (45 mg, 0.14 mmol Mo ears). The reaction mixture was stirred for 3 hours followed by the addition of L-proline tert-butyl ester. (15 mg, 0.088 mmol). The reaction mixture was mixed overnight. The reaction mixture was poured directly into an Isolute column (2 g, silicone). The product makes the angle DCM:

EtOAc <RTI ID=0.0></RTI> </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; M/z 793.2. Method 11 1,1-Oxo-3,3-dibutyl-5-stupid-7-methylthio-8-(~1^-{(foot)-〇:-[义(三丁Gas carbonyl, a methyl group, a N-methylamine, a methyl group, a fluorenyl group, an amine, a methyl group, a methoxy group, a metal sulfonyl group 1,1-oxo-3,3-dibutyl-5-styl-7-methylthio-8-[&gt;1-((11)-(3: citricyl)amino) Mercaptooxy]-2,3,4,5-tetrahydro-1,2,5-benzopyrimidine (Example 25; 50 mg, 0.078 mmol) and N-mercapto Gan Tert-butyl citrate (15 mg '0.10 mmol) in DCM (2 mL) and N-mercaptomorpholine (17.2 μl, 0.156 mmol) and TBTU (45 mg, 0.14 mmol) The reaction mixture was stirred for 4 hours. The reaction mixture was poured directly onto a Is 〇iute column (2 g, yt). The product used DCM ··EtOAc, 1 〇〇: 〇, 95:5, 90: 10 and then 80: 20 The title compound (3 mg, 50%) was obtained by gradient elution. M/-z 767.4. Method 12 1,1·~--------- 107- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm)

k 1331143 A7 B7 V. Description of invention (1〇5

Ll-(R)-2-(R)-lf tert-butoxycarbonyl)-1-hydroxypropan-2-yl 1aminocarbazide} mercapto)aminocarboxamide a gas base 2,3 ,4,5-tetrakis-1,2,5- benzopyrrolidine 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-[ N-((R) - α thiopurinyl)aminomethionylmethoxy]-2,3,4,5-tetrahydro-1,2,5-benzothiazepine (example) 25; 50 mg, 0.078 mmol; and (2R, 3R)-3; tert-butyl amino-2-hydroxybutyrate (15 mg, 0.086 mmol) dissolved in DCM (2 mL) and DMF ( In 1 ml), N-mercaptomorpholine (17.2 μl, 0.156 mmol) and TBTU (45 mg, 0.14 mmol) of P reaction mixture were stirred for 4 hours. The reaction mixture was poured directly into the Isolute column. The title compound (33 mg, 53%) was obtained using EtOAc (EtOAc: EtOAc) /z 797.3. Method 13 N-((2R)-2-丨 "(Indolyl)carbonyl 1Amineyl-2-phenylamino)-o-indenyl butyl)-L-serine Tributyl ester (2R)-{[(decyloxy)carbonyl]amino}(phenyl)acetic acid (2.0 g, 7_0 mmol) O-(t-butyl)-L-serine tert-butyl ester (2.0 g, 7.9 mmol) and 2,6-lutidine dissolved in 〇〇1^ (30 ml). At 0° (After stirring for 5 minutes, TBTU (2.5 g, 7.8 mmol) was added and stirring was continued for 30 minutes at 〇 ° C and at room temperature for 4 hours. The reaction mixture was washed with water (2×100 mL), dehydrated and The title compound (3.3 g, 97%) was obtained by flash chromatography (EtOAc). NMR (300 MHz): 1.05 (s, 9H), 1.45 (s, 9H), 3.4-3.8 (m, 2H), 4.5 (brs , 1H), 4.85 (s, 2H), 5.1 (s, 2H), 5.4 (s, 1H), 7.25-7.5 (m, 10H). -108- This paper scale adopts Chinese National Standard (CNS) A4 specification (210X297 mm)

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Line 1341143 A7 B7 V. Description of the invention (1〇6) Method 14 N-rCjR) _-2-Aminoethyl hydrazine ortho-tertiary tert-butyl) _^Sisminamine tert-butyl ester N-((2R) -2-{[(芊-oxy)carbonyl]amino-2-phenyl-2-ylphenyl)-tert-(t-butyl)-L-serine tert-butyl ester (Method 13; 3 3 g, 6.8 . millimolar) dissolved in EtOH (953⁄4 '30 ml) and added catalytic amount pd / c (5%) (50% in water) and hydrogenated at room temperature for 3 hours at room temperature β reaction mixture filtered through Shixia thin soil The title compound (2.35 g, 98%). NMR (500 MHz): 1.1 (s, 9H), 1.45 (s, 9H), 3.45-3.8 (m, 2H), 4.5 (t, 1H), 4.55 (s, 1H), 4.85 (s, 2H), 7.3-7.5 (m, 5H). Method 15 1,1^ oxo-2-[4-methoxyindole&gt;)_3,3_dibutyl-5-styl-7_methyl_8-oxime_oxy_^-2 ,3,4,5-tetraki-1,2.5-mosa#pyridine dioxime due to 1,1-dioxo-2(4-decyloxyindenyl)-3,3-dibutyl- 5-phenyl-7-bromo-8-methoxy-2,3,4,5-tetrahydro-1,2,5-benzopyrimidine (Method 23; 2.1 gram ' 3.41 mmol Th) (50 ml) of a cooling solution (-78), a solution of 11-6111^ (2_35 ml, 3.75 mmol, 1.6^1 in hexane) was added dropwise. After stirring at _78 °C for 20 minutes Mel (2.42 g, 17.1 mmol) was added. The mixture was stirred at -78 ° C for 1 hr and at room temperature for 18 h. Ethyl ether (50 mL) and organic phase with 10% NH4C1 (50 mL Wash with brine (50 ml). After dehydration, filter and concentrate.

EtOAc </RTI> <RTI ID=0.0></RTI> </RTI> <RTIgt; NMR (300 MHz, CDC13): 0.60-0.70 (m, 6H), 0.70-0.90 (m, 4H), 〇.9〇. 1.35 (m, 8H), 2.00 (s, 3H), 3.70 (s, 3H ), 3.80 (s, 3H), 4.00-4.20 (m&gt; -109- This paper scale applies to China National Standard (CNS) A4 specification (210X 297 mm) 1331143 A7 B7 V. Invention description (1〇7) 2H ), 4.35-4.60 (m, 2H), 6.65-6.85 (m, 3H), 6.90-7.10 (m, 3H), 7.15-7.30 (m, 5H). Method 16 LJ.--.Dioxo-3,3·dibutyl_5_Stupid·7-Methyl-8-carboxyoxime O. 2,3,4,5-tetrahydro-1,2.5 Adding 1,1-dioxo-2-(1) to a solution of trimethylacetic acid (30 ml) and triethyl decane (1.03 g, 8.85 mmol) (0 ° C) 4-methoxyindenyl)-3,3-dibutyl-5-phenyl-7-methyl-8-decyloxy-2,3,4,5-tetrahydro-1,2,5- A solution of benzopyrazine (Method 15; 〇_92 g, 1.77 mmol) in DCM (2 mL). The reaction mixture was stirred at room temperature for 30 min. EtOAc (EtOAc m. After dehydration, filtration and concentration, the crude product was subjected to EtOAc (EtOAc:EtOAc:EtOAc A solution of BBr3 in DCM (1M in DCM &lt;RTI ID=0.0&gt;&gt; The reaction mixture was stirred at room temperature for 45 min then washed with sodium bicarbonate (10%, 25 mL) After dewatering, filtration and concentration, EtOAc (EtOAc m. Solution was added MK2C03 (0.22 g, 1.58 mmol) and tetra-n-butylammonium bromide (10 mg) followed by ethyl bromoacetate (0.25 g, 1.51 mmol). The reaction mixture was stirred at 80 ° C for 1.5 hr then concentrated under reduced pressure. The residue was dissolved in EtOAc (50 mL)EtOAcEtOAcEtOAc After dehydration, filtration and concentration, EtOAcqqqqqq This solid is dissolved in THF:H20 (4: 1,25 ml) and added with LiOH (0.097 g, 2.31 mmol 110-this paper scale applies to Chinese National Standard (CNS) A4 specification (210X297 mm) 1331143 A7 B7 V. Description of the invention (108) Ear). The reaction mixture was stirred at room temperature for 40 minutes. The mixture was evaporated under reduced pressure, taken in water (EtOAc) The aqueous layer was extracted twice with diethyl ether. Evaporation of the solvent <RTI ID=0.0> NMR (300 MHz, acetone-d6): 0.70-0.90 (m, 6H), 0.95-1.80 (m, 12H), 2.15 (s, 3H), 3.85-4.15 (m, 2H), 4.85 (s, 2H) , 6.00 (s, 1H), 6.80 (s, 1H), 6.90-7; 05 (m, 1H), 7.10-7.45 (m, 5H). Method 17 (R)-N-helium carbonyl-α-ankyl-4-hydroxyindole (R)-p-hydroxyphenylglycine (5.00 g, 29.9 mmol) mixed with water (50 ml) . Sodium bicarbonate (6.3 g, 75.0 mmol) was added to the slurry and fluffed; a white suspension was obtained after 10 min. Gas benzyl formate (5.1 ml, 3 3.9 mmol) was added from the dropping funnel over 20 minutes and the mixture was stirred vigorously. After 2 hours, water (300 ml) was added and the suspension was extracted with diethyl ether (200 ml). The white solid did not dissolve and added more water and B35. LC/MS showed the solid as the product. The transparent portion of the aqueous phase was collected and acidified to form a white precipitate. Place it for another weekend at the end of the week and then filter. The remaining aqueous phase containing the undissolved material was acidified and extracted with EtOAc (3x). There is also a deposit between the phases. Collect organic layers. The EtOAc phase was evaporated. Toluene 2x was added to remove water. The twice collected white hot solids were collected and recrystallized from DCM (200 mL). The cooled mixture was filtered and 4.77 g (53%) of white solid. NMR (400 MHz, DMS0-d3): 5.00 (1H, d), 5.00 (2H, s), 6.70 (2H, d), 7.05-7.50 (7H, m), 7.90 (1H, d) » Method 1 8 Oxycarbonyl-α-{&gt;|-(8)-1-(Third-butyl carbonyl)propyl 1胗-111 - This paper scale applies to Chinese National Standard (CNS) Α4 specification (210 X 297 MM)

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Line 1331143

d), 8·15 (1H, d). Method 20 generation-5-stupyl-7-methylthio-8-(Ν-ΠΙ〇-α 丨 tributary decyl (third butyl carbonyl) ethoxy 1 aminomethyl aryl} hydrazinyl 1 fluorenyl }aminomethyl hydrazine methoxy) two 2.3.4.5- four fish 1,1-oxo-3,3-dibutyl _5-styl -7-methylthio-8-(&gt;^ -{(11)-〇:[1^-((S)-l-propenylpropyl)aminoindolyl]nonylaminomethylmercaptomethoxy)_2.3.4.5-tetrahydro- i,2,5- benzothiazepine (example 6, 15 mg, 〇〇21 mmol), 0-(t-butyl)_L_serine tert-butyl ester hydrochloride (5 4 mg '0.021 mmol) and n-methylmorpholine (46 μl, 〇〇42 mmol) were dissolved in DMF (1 mL). TbtU (12.5 mg, 0.039 mmol) was added and the mixture was mixed for 1 hour. 〇_(Third butyl)_L_serine tert-butyl ester hydrochloride (0.8 mg '〇.〇〇31 mmol) was added and the mixture was stirred for several minutes. The solvent was distilled off under reduced pressure and distilled with toluene for several minutes. The product was purified using a pre-packed ISOLUTE column (gum, 2 g) using DCM: EtOAc, 100: 〇 (10 mL), 95:5 (10 mL), 90:10 (10 mL) ' 80:20 (10 ML) Gradient gradient elution afforded 14 mg of the title compound. M/z 924.7. Method 21 1.1-Dioxo-3.3-dibutyl-5-styl-7-indolethio-8-(]^-((10-〇-"2-(S)-2_-_(曱氧Carbonyl, _4-m-4-(hydroxy)pyrrolidin-1-one 耧1芊1 1 aminocarbazinyl anthracene)-2.3.4.5·tetrahydro-1,2,5-benzopyrimidine Indole due to 1,1-dioxo-3,3-dibutyl-5-phenyl-7-indenyl-8-[N-((R)-Q:-carboxyindenyl)amine Mercaptooxy]-2,3,4,5-tetrahydro-1,2,5-benzopyrimidine 113- This paper scale applies to Chinese National Standard (CNS) A4 specification (21〇x 297 mm) )

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Line 1341143 A7 B7 V. Description of the invention (111) Gyne (Example 25; 54 mg, 0.084 mmol), (4R)-4-hydroxy-L-proline methyl ester hydrochloride (18.4 mg, 0.10 m) Mole) and ]^• Mercaptomorpholine (13 9 μl '0.13 mmol) dissolved in DMF (2 mL). TBTU (32.5 mg, 0.101 mmol) was added and the mixture was stirred for 3 hours. The solvent was distilled off under reduced pressure. The product was purified twice using a pre-filled ISOLUTE column (tank, 2 g) and used 0〇\4: £10 八&lt;:, 100:0'95:5, 90:10, 80:20 and 60:40 Gradient gradient elution. Obtained 23 mg of the title compound. M/z 767.〇. Method 22 1^-Di-deutero-313-dibutyl-5-styl-7-methylthio-8-(]^-{(foot)-(3:-『2-Lg) -2-( Third butanol pen _ base) 吖 啶 丨 丨 某 某 某 某 某 某 某 } } } } } } } } 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 2.3 , , , , , , , , ,1-dioxo-3,3-dibutyl-5-phenyl-7-indolyl-8-[N-((R)-α-carboxy-henyl)aminoindenyloxy ]_2,3,4,5-tetrahydro-1,2,5-benzoxaindole (Example 25; 50 mg, 0.078 mmol), (2S)-azetidine-2-carboxylic acid The third vinegar (17.4 mg, 0.111 mmol) and Ν_mercaptomorpholine (1 〇 3 μl '0.094 mmol) were dissolved in DMF (2 mL). TBTU (30 mg, 0.094 mmol) was added and the mixture was stirred for 4 hours. The solvent was distilled off under reduced pressure. The product was purified using a pre-packed ISOLUTE column (gum, 2 g) and using DCM: EtOAc &gt; 10 〇: 〇^ 95:5' 90: 10 &gt; 80: 203⁄4 ^ # 27.5 mg of title compound m/z 777.6 (MH)·. Method 23 LJ-SO-oxo-2-(4-oxime oxime)-3,3-dibutyl-5-mosyl-7-bromo-8-fluorenyl-2,3,4,5 - four chaos -1,2,5 - stupid and p窠 two p丫 heptane due to 1,1-dioxo-3,3-dibutyl-5-phenyl-7-bromo-8-methoxy -2,3,4,5-four_____-114- This paper size is applicable to the SS standard (CNS) A4 specification (21GX 297 public) 1331143 A7 B7

Adding p-methoxyl base gas (0.066 ml) to a solution of argon-1,2,5-propenyl p-dihexyne (according to WO 98/38182; 0.200 g, 0.404 mmol) in MeCN (5 ml) , 0.486 mmol) Csl (0.010 g, 0.038 mmol) and Cs2C03 (0.263 g, 0.807 mmol) and the mixture was stirred at 6 ° C for 4 hours. The solvent was removed under reduced pressure and the residue was partitioned between EtOAc and EtOAc. The organic layer was washed with brine and dehydrated and concentrated with MgS 4 . The residue was purified by EtOAc (EtOAc:EtOAc) NMR (400 MHz, CDCl3): 0·60_ 0.75 (m, 6H), 0.75-1.20 (m, 8H), 1.25-1.45 (m, 2H), 1.80-2.00 (m&gt; 2H), 3.80 (s, 3H) ), 3.90 (s, 3H), 4.05-4.30 (m, 2H), 4.45-4.65 (m, 2H), 6.70-7.45 (m, 11H). Method 24 1,1-dioxo-2-(4-carbamoyl)-3,3-dibutyl-5-styl-7-carbamyl-8-hydroxy-2,3,4.5 - four i.-1.2.5- stupid and ambiguous

NaSMe (〇.150 g, 2.03 mmol, 95%) was added to 1,1-dioxo-2-(4-methoxybenzyl)-3,3-dibutyl-5-phenyl- 7-Bromo-8-decyloxy-2,3,4,5-tetrahydro-1,2,5-benzoxaindole (Method 23; 0.249 g, 0.404 mmol) of DMF (5 ML) solution. The mixture was stirred at RT for 2 hours, then the temperature was raised to 80 ° C and more NaSMe (0.090 g, 1.22 mmol) was added. After 20 hours at 80 ° C, water (5 ml) and 1 M HCl (water solution) (pH about 4) were added to the mixture. The solution was washed 3 times with Et 2 and the combined organic layers were washed with brine, dried and concentrated with EtOAc. The crude product was purified by flash chromatography eluting elut elut elut elut elut elut NMR (500 MHz, CDC13): 0.60-0.75 (m, 6H), 0.75-1.20 -115- This paper size applies to Chinese National Standard (CMS) A4 size (210 x 297 mm) 1331143 A7 _____B7 V. Description of invention ( 113 ) (m, 8H), 1.25-1.40 (m, 2H), 1.80-2.00 (m, 2H), 2.20 (s, 3H), 3.80 (s, 3H), 4.20 (brs, 2H), 4.50 (brs , 2H), 6.05 (brs, 1H), 6.75-6.85 (m, 3H), 7.00-7.10 (m, 3H), 7.20-7.35 (m5 4H), 7.50 (s, 1H) » Method 25 U-dairy -2-(4-methoxyindolyl)-3,3-dibutyl _5_ 茉 _7_ 曱 某 _ 8-(second butyl carbonyl oxime)-2,3,4 ,5-tetrahydro-L's-laughing and scorpion quinone 0_ 1,1-dioxo-2-(4-decyloxyindenyl)-3,3-dibutyl-5-phenyl-7 -Methylthio-8-hydroxy-2,3,4,5-tetrahydro-1,2,5-benzothiazepine (Method 24; 4.487 g ' 7.889 mmol) MeCN (100 ML) solution was added with second butyl bromide (0.262 g '0.813 mmol), butyl bromoacetate (146 ml '9.8880 mmol) and potassium carbonate (anhydrous ' 3.28 g, 23.7 mmol) . The mixture was heated to 55 °C for 2.5 hours, then cooled to rt and stirred overnight. The solvent was evaporated until a yellow syrup was maintained, which was extracted between diethyl ether (150 mL) and water (100 mL). The aqueous phase was washed with diethyl ether (丨 00 mL) and combined and washed with &lt;RTI ID=0.0&gt;&gt; The ether was removed under reduced pressure and the obtained brown solid was dried under reduced pressure for 4 hours (5,355 g, 99%). NMR (400 MHz, CDC13): 0.60-1.25 (m, 14H), 1.25-1.40 (m, 2H), 1.50 (s, 9H), 1.75-2.00 (m, 2H), 2.10 (s, 3H), 3.80 (s, 3H), 4.20 (brs, 2H), 4.50 (brs, 2H), 4.60 (s, 2H), 6.45 (s, 1H), 6.75-6.85 (m, 2H), 7.00-7.15 (m, 3H ), 7.20-7.40 (m, 5H). — Method 26 1,1-dioxo-3.3-dibutyl-5-styl-7-methylthio-8-(N-(fm· α -ΓΝ- ___-116- This paper size is applicable Solid National Standard (CNS) Α4 Specifications (210X 297 mm) 1331143 A7 B7 V. Description of Invention (114)

Lis)-1-{N-丨(S)-l-(t-butoxycarbonyl)ethylamine A certain methyl hydrazide hydrazine, I yl yl yl 1某)_2 3 4 Four arrows _ 彳? Stupid and exhausted 1,1-dioxo-3,3-dibutyl-5-styl-7-indolethio-8-[1^-((foot)-«_carboxyl Aminomethylmercapto methoxy] 2,3,4,5-tetrahydro-1,2,5-benzothiazepine (Example 25, 58 mg, 0.091 mmol), L- Alanine-L-alanine second. Butyl ester hydrochloride (27.5 mg '0.11 mmol) and N-mercaptoline (20 μl '0.18 mmol) dissolved in DMF (2 mL) . Add TBTU (.35 mg, 〇. 1 8 mmol) and stir the mixture for 2-3 hours. The solvent was distilled off under reduced pressure. The product was purified using a pre-packed ISOLUTE column (2 g), using DCM: EtOAc, EtOAc: EtOAc, EtOAc: EtOAc: Compound. M/z 838.5. Method 27 Methyl leucine tributyl sulphate 4-methyl leucine (500 mg, 3.44 mmol) was suspended in 1 liter of tributyl acetate. Adding high gas acid (〇·2 ml, 3.49 mM) Moll) and the bottle were stoppered and stirred overnight. Analysis was carried out using TLC (DCM: MeOH, 9:1; coloured with indanetrione/EtOH solution). The solution was poured into a flask containing 3 ml of EtOAc and 30 ml of 5% Na2C03. The aqueous layer was converted to acidity and 2M NaOH was added until a pH of about 7. The separated phase and aqueous phase were washed with 2×30 mL EtOAc. The combined organic phase was washed with brine, dehydrated and evaporated with Na2SO4. The oil obtained was co-evaporated with toluene and then co-evaporated with diethyl ether and placed in vacuo for 2 days. Mass 665 mg (96% yield). NMR (CDCl3): 1.0 (s, 9H), 1.5 (s, 9H), 1.65-1.95 (m, 2H), 3.82 (t, 1H). ______-117- This paper size applies to China National Standard (CNS) A4 specification (210 X 297 mm) 1331143 A7 B7 V. Description of invention (115) Method 28 3-(三曱基石夕基) Alanine cool 3-trimethyl sulphonic acid alanine (J. 〇rganomet chem., 628,

(2001) '183-194; 19 mg, 0.118 mmol) and 3 ml of BF3-MeOH (14%, 3.7 mmol) were mixed in a sealed tube and heated to 7 °C. Analysis was carried out using TLC (MeOH.DCM 1:9, coloring with ethanol of indane). The mixture was heated for 3 hours and then cooled to ambient temperature. The mixture was poured into a mixture of 3 mL EtOAc and EtOAc (EtOAc). Additional Na2C03 (5%-water solution) was added until a pH of about 7. The aqueous phase was washed with EtOAc (2×3 mL). The combined organic layers were washed with brine (1 mL) and evaporated and evaporated. The product of the white film was obtained. Mass: 19 mg (92% yield) NMR (CDC13): 0.1 (s, 9H), 1.2-1.4 (m, 2H), 3.8 (s, 3H), 4.2 (brs, 1H). -118- This paper size is applicable to China National Standard (CNS) A4 specification (210X 297 mm) 1331143 Application deadline ^/. 9. ^. Case number 091120297 Category 〆 月 月?曰

A4 C4

V ·, ^ V , on the book H4 August) f 3 patent specification

Benzopyrazine derivative, preparation method thereof and pharmaceutical composition containing the same ', BENZ AND Pi 0THIADIA2EPINE DERIVATIVES, PROCESS FOR PREPARING THEM 'HARMACEUTICAL composition included them , , Lin | Name English name Nationality invention invention 1_英吉马史塔克 2. McDownstone 3. Daweibroberger 4. Susan Slangak 5. Tolshi Zari 6. Majule Murray

INGEMAR STARKE MIKAEL DAHLSTROM DAVID BLOMBERG SUZANNE ALENFALK TORE SKJARET MALIN LEMURELL Residence, Residence Name (Name) Nationality

1· 3. 4. 6. Both Sweden SWEDEN

2. Finland FINLAND 5. Norway NORWAY

1.-6. No. i, Pepari Sledon Street, Mondell, Sweden PEPPAREDSLEDEN 1, 431 83 MOLNDAL, SWEDEN British company AstraZeneca UK Co., Ltd. ASTRAZENECA UK LIMITED

UK UNITED KINGDOM III. Applicant Residence, Residence (Company)

15 Stanhope Road, London, UK 15 STANHOPE GATE, LONDON, W1K 1LN, UNITED KINGDOM Representative Name

Linda May Slack LYNDA MAY SLACK This paper size applies to China National Standard (CNS) A4 specification (21〇x 297 mm)

1331143 Patent Application No. 091120297 Replacement Page (August, 1993) V. Invention Description (!) The present invention relates to a benzopyrazine and benzothiazepine derivative or its pharmaceutical acceptability Salts, solvates, solvates of such salts and prodrugs thereof. These benzothiazepines and benzopyroxyin have ileal sulphuric acid transfer (IBAT) inhibitory activity and are therefore of value for treating disease states associated with hyperlipidemia conditions and are useful for treating warmth The method of blood animals such as humans. The present invention is also directed to a method of producing the benzopyrazine derivative, a pharmaceutical composition containing the same, and a pharmaceutical use thereof for inhibiting IBAT in a warm-blooded animal such as a human. Elevated total cholesterol, very low-density lipoprotein cholesterol, high-grade a-massemia is a major risk factor for cardiac and arteriosclerotic diseases (eg "coronary heart disease: reducing risk; global review, Assman G.,

Carmena R. Cullen P. et al; Circulation, 1999, 100, 1930-1938 and "Diabetes and Cardiovascular Diseases: American Heart Association Health Professional Statement",

Grundy S, Benjamin I., Burke G., et al., Circulation, 1999, 1〇〇, 1134-46). Interfering with bile acid circulation in the lumen of the intestine can reduce cholesterol levels. Previously established therapies for lowering cholesterol concentrations include, for example, treatment with HMG-CoA reductase inhibitors, preferably statins such as simvastatin and fluvastatin, or bile acids. Adhesives such as resins. Commonly used bile acid binders are, for example, cholestyramine and cholesipol. A therapy has recently been proposed ("Bile acid and lipoprotein metabolism: a renaissance of bile acids in the late stages of statin" Angelin B, Eriksson M, Rudling Μ; Modern Insights in Lipidology, 1999, 1〇, 269-74) Substance treatment with anti-inhibition effect. Reabsorption from bile acids in the gastrointestinal tract is a normal physiological process that occurs primarily in the ileum by the IB AT metabolic system. Antimony inhibitors can be used to treat high-solid paper standards for the Chinese National Standard (CNS) A4 specification (210X 297 mm)

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1331143 Patent application No. 091120297 Chinese manual replacement page (August, 1993) V. Description of the invention (20) 2-propynyl group. Examples of "N-CCw alkyl) aminsulfonyl" and "N^Cw alkyl" amine sulfhydryl groups are N-(C 1_3)-based amine olefins, N-(methyl)amine acid groups. And N-(ethyl)amine sulfonyl. Examples of "N-CC!.6 alkyl)2aminesulfonyl', and "alkyl"2aminesulfonyl" are N,N-(didecyl)aminesulfonyl and N-(fluorenyl) Examples of the _N_(ethyl)amine sulfonyl group "N-CCw alkyl" amidino group, and the "N-CCij alkyl group" of the amine mercapto group are a mercaptoaminocarbonyl group and an ethylaminocarbonyl group. "N,N_(Cw alkyl)2amine-carbamoyl" and "Ν,Ν^ί:^alkyl"2 amine fluorenyl, examples are dimethylaminocarbonyl and decylethylaminocarbonyl . The "Cw alkylsulfonyl group" is a methylsulfonyl group and an ethylsulfonyl group. "(Cw alkyl) 3 fluorenyl group, and examples include a trimethyl decyl group and a methyl diethyl fluorenyl group. Suitable pharmaceutically acceptable salts of the compounds of the invention are, for example, acid addition salts of the compounds of the invention which are sufficiently basic, such as acid addition salts with inorganic or organic acids, such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid, Fluoroacetic acid, citric acid, acetic acid or maleic acid. Furthermore, suitable pharmaceutically acceptable salts of the compounds of the invention which are sufficiently acidic are metal salts, for example, nano or oblique salts, soil metal salts such as calcium or magnesium salts, ammonium salts or organics which provide physiologically acceptable cations. The salt formed is tested, for example, with a salt of methylamine, dimethylamine, tridecylamine, brigade, chlorpyrifos or tris-(2-hydroxyethyl)amine. The compound of formula (I) can be cleaved in human or animal to obtain a prodrug of a compound of formula (&gt;). Examples of prodrugs comprise in vivo hydrolysable g of a compound of formula (I) and in vivo hydrolysable guanamine. An in vivo hydrolysable ester of a compound of formula (I) containing a tick or light base is a suitable pharmaceutically acceptable ester of a pharmaceutically acceptable ester beta carboxyl group which is hydrolyzed, for example, in a human or animal to produce a crude acid or alcohol, comprising Cl-6. Alkoxymethyl esters such as decyloxymethyl-23- This paper scales for the right S @ 辟 (CNS) A4 specifications (21GX 297 mm) 1331143 No. 091120297 patent application Chinese manual replacement page (93 years 8 Month) A7 Amendment 5, Invention Description (1〇9)

Brewing base 丨 4-hydroxy 胗 胗 (11)-]^-; oxycarbonyl-0; _ carboxy 4-hydroxy decylamine (Method 17; 2. gram, 6.64 millimoles), (2S a solution of tert-butyl 2-aminobutanoic acid (1.30 g, 6 64 mmol) and N-mercaptomorpholine (2.0 g ' 19.8 mmol) 〇〇^ (30 ml) in RT Stir for 5 minutes, then add TBTU (2.60 g, 8.1 Torr). The reaction mixture was given a whip separator at ambient temperature. The solvent and residue were removed under reduced pressure and purified by flash chromatography (DCM:EtOAc: 60:40). The product was crystallized from toluene (20 mL). NMR (400 MHz): 0.80 (3H, t), 1.45 (9H, s), 1.50-1.80 (2H, m), 4.10-4.20 (1H, m), 5.05 (1H, d(AB)), 5.15 ( 1H, d(AB)), 6.75 (2H, d), 7.20-7.40 (7H,m) »Method 19 £^) - a -{Nr(S)_丨彳笛三丁气carbonyl)propylamine Alkylamine (11)-;^-oxime oxycarbonyl-0:-{]^-[(8)-1-(t-butoxycarbonyl)propyl]aminocarbazinb A mixture of hydroxyguanamine (method 18; 1.80 g, 4.07 mmol) and Pd/C (0-2 g, 5%) in ethanol (30 mL, 95%) was stirred at room temperature for 2 hr. The reaction mixture was filtered through EtOAc (2 g) and concentrated. The residue was dissolved in acetone (20 mL) and methanesulfonic acid (0.40 g, 4.16 m). No crystallization was obtained and the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC using 20-50% MeCN in 0.1 M ammonium acetate gradient buffer as the solvent. The title compound was obtained as a white solid (0.35 g). NMR (400 MHz, DMSO-d6): 0.75 (3H, t), 1.40 (9H, s), 1.50-1.75 (2H, m), 2.70 (1H, s), 4.00-4.10 (1H, m), 4.30 (1H, s), 6.65 (2H, d), 7.15 (2H, 112 This paper size applies to the Chinese National Standard (CNS) A4 specification (210 X 297 mm)

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Claims (1)

1331143 Patent Application No. 091120297 Chinese Patent Application Substitute (June 1999) VI. Scope of Application 1. A compound of formula (I) or a pharmaceutically acceptable salt thereof, Wherein: Rv is selected from hydrogen; one of R1 and R2 is selected from Cu alkyl and the other is selected from C丨 alkyl; R x and R y are hydrogen; lanthanide is -N -; ν is 0 One of R4 and R5 is the base of formula (ΙΑ): (ΙΑ) R3 and R6 and the other R4 and R5 are independently selected from hydrogen, halo, C1.4 alkyl or (^.4 alkyl S(0)a, where a is 0; 80189-990618.doc -1 - This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 1331143 A8 B8 C8 D8 VI. The scope of application for patent X is -〇-; where ring A is selected from one or more selected from R 1 Ring A is phenyl; a substituted group; R7 is hydrogen; R8 is hydrogen; R9 is hydrogen; R is a carboxyl group; or R&quot; is a group of formula (IB) or (1C): Y is _N(Rn)C(0)-; wherein R_n is hydrogen; R12 is hydrogen or Ci_4 alkyl; 14 further selected R13 and R14 are independently selected from hydrogen or Cb6 alkyl; and when q is hydrazine, optional From the hydroxyl group; wherein RI 3 and R 14 may be independently substituted by one or a substituent from R 2 G; R 5 is a slow or a repeat; p is 1 or 2; wherein the value of R 13 may be the same or different; q is 0 r is 0 or 1; m is 〇; π is 1; 1 -yl ring B is a carbon bite substituted by a group selected from R 2 3 to be bitten 80189-990618.doc This paper scale applies to Chinese national standards (CNS) A4 size (210x297 mm) 1331143 A8 B8 C8 D8 VI. The scope of patent application or azetidine-1-yl group, and optionally one or more KM generations on carbon; R 1 7 is the R and R are independently selected from the group consisting of a trans-group, an amine group, an amino-based aryl group 'ey alkyl S(〇) a (where &amp; is 0), an oxo group or a (Cn alkyl) 3 Shi Xi Xuanji; and R23 is a carboxyl group. 2. A compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein the R1 and R2 are both butyl. A compound of the formula (1) or a pharmaceutically acceptable salt thereof, wherein R3&amp;R6 is hydrogen. 4. A compound of the formula (1) or a pharmaceutically acceptable salt thereof according to the scope of claim 2 or 2, wherein R 4 is bromo, methyl or sulfonylthio. 5. A compound of formula (j) or a pharmaceutically acceptable salt thereof as claimed in claim 2 or 2 wherein R 5 is a group of formula (IA) (as described in claim 1), wherein: X is -0 -; ring A is a phenyl group optionally substituted with one or more substituents selected from R 1 7; η is 1; R 7 is milk; R 8 is hydrogen; R 9 is hydrogen; m is 0; -990618.doc This paper size applies to China National Standard (CNS) A4 specification (210x297 mm) 1331143 A8 B8 C8 ____ D8 VI. Patent application scope R11 is carboxyl group, formula (IB) base (as above) or formula (1C) The base of (as described above); wherein: R12 is hydrogen or c 1.4 alkyl; P is 1 or 2; R is hydrogen or optionally substituted by R2G, wherein R2 is a hydrazine, amine a mercapto group, an amine group, an aryloxyamino group, an alkyl group S(〇)a (where a is 〇) or (Ci.4 alkyl) 3矽 alkyl; R14 is hydrogen or a hydroxy or C^6 alkane Wherein RH may be optionally substituted with - or a plurality of substituents selected from R20; Y is -N(Rn)C(0)-, wherein R_n is hydrogen; q is 0; r is 0 or 1; R15 is a carboxyl group; Or sulfo; R17 is hydroxy; and R2Q is selected from a hydroxy group; a ring B is a pyrrolidinium- or azetidinyl group substituted on the carbon by a group selected from R23 and optionally substituted with one or more R2 4 on the carbon; wherein R23 is a carboxyl group and R24 is a hydroxyl group. . 6. A compound of the formula (1) or a pharmaceutically acceptable salt thereof according to the scope of the invention, wherein: Rv is hydrogen; R1 and R2 are both butyl; Rx and 1 are both hydrogen; -N-; 80189-990618.doc 1331143 Δ8 /\ο Β8 C8 D8 VI. The scope of application for patent v is Ο; R3 and R6 are hydrogen; R4 is bromo, methyl or sulfonyl; and R5 is N-{(R)-a-[N-( Carboxymethyl)aminoindenyl]benzyl}aminoindenyloxy, N-{(R)-a-[N-(2-sulfoethyl)aminoindenyl]-4 -hydroxybenzyl}aminoindenyloxy, N-{(R)-a-[N-((S)-1-carboxy-2-hydroxyethyl)aminoindenyl]benzyl} Aminomethyl methoxy methoxy, N-{(R)-a-[N-((S)-l-carboxyethyl)amino fluorenyl]benzyl}amino fluorenyl methoxy, N-{(R)-a-[N-((S)-l-carboxypropyl)aminocarbonyl]carbonyl}aminocarbonylcarbonyl, N-{(R)-a- [N-((R)-l-carboxy-2-indolyl-ethyl)aminoindenyl]nonyl}aminodecylmethoxy, N-{(R)-a-[N -((S)-l-carboxy-2-aminoindolyl-ethyl)aminomethylindenyl]benzyl}aminomethylindenyloxy, N-{(R)-a-[N -(carboxydecyl)aminomercapto]-4-hydroxybenzyl}aminomercaptomethoxy, N-{(R)-a-[N-((S)-l-carboxyethyl Aminomethyl]-4-hydroxybenzyl}aminoindenyloxy, N-{(R)-a-[N-((S)-l-carboxy-2-hydroxyethyl) amine Alkyl]-4-hydroxyindole}aminoalkylcarbonyloxy, N-{(R)-a-[N-(2-sulfoethyl)aminoindenyl]benzyl} Aminocarbonylcarbonyl, N-{(R)-a-[N-((S)-l-carboxy-2-(R)-hydroxypropyl)aminoindenyl]benzyl}amine Base methoxy, N - {(R)-a-[N-((S)-l-carboxy-2-mercaptopropyl)amino fluorenyl]benzyl}amino fluorenyl Anthraceneoxy, N-{(R) - a - [N-((S)-1-carboxy-3-mercaptobutyl)aminocarbonyl] fluorenyl}aminocarbonylcarbonyl, N- 80189-990618.doc -5- This paper size is applicable to China National Standard (CNS) A4 specification (210x297 mm) 1331143 as Β8 C8 D8 _ 6. Patent application scope {(R) - a - [N-(1 -(S)-1-carboxy-2-(S)-2-mercaptobutyl)aminocarbonyl]hydrazino}aminocarbonylcarbonyl, N-((R)-a-carboxyl 4-hydroxybenzyl)aminocarbamidomethoxy, N-{(R)-a-[N-((S)-l-carboxy-4-aminobutyl)aminocarbonyl] N-((R)-a-{N-[(S)-l-carboxyl((oxycarbonylamino)butyl]amino) N-[(R)-o:-((S)-2-carboxypyrrolidin-1-ylcarbonyl) Amino]aminocarbonyloxy, N-{(R)-a-[N-(carboxyindenyl)-indolylaminocarbonyl]benzyl}aminoindenyloxy , N-{(R)- a - [N-(l-(R)-2-(R)-Bucarboxy-1-hydroxypropan-2-yl)aminoindenyl]benzyl}amino曱醯 曱 曱 、, N-{(R)-〇:-[N-(sulfoalkyl)aminocarbonyl] fluorenyl}aminocarbonylcarbonyl, N-((R) -a-carboxybenzyl)aminocarbamidomethoxy, N-{(R) - a - [N-((S)-1-carboxy-2-(R)-hydroxypropyl)amino) Indolyl]-4-hydroxybenzyl}aminomercaptomethoxy, N-{(R)-a-[N-((S)-1-heptyl-2-mercaptopropyl)amine [曱醯]]-4-hydroxybenzyl}aminomethylindenyloxy, [N-((S)-1-carboxybutyl)aminocarbamimidyl]-4-hydroxybenzyl}aminopurine Mercaptomethoxy, N-{(R)-a-[N-((S)-l.carboxypropyl)aminoindenyl]-4-yl-based group}amino-based methoxyl , [N-((R)-1-sulfoyl-2-oxiranylethyl)aminomethylindenyl]_4_yl-based aryl methoxy, N-{(R )__[N-((S)-1-Zipylpropyl)aminoglycolyl]-4-hydroxybenzyl}amine-based oxime-based oxime, N-{(R)-a-[ N-{(S)-l-[N-( (S)-2-Hydroxy-1-carboxyethyl) Amine-based aryl]propyl}amino-based aryl-based amine group aryl-based oxy- 6-80189-990618.doc Applicable to China National Standard (CNS) A4 specification (210x297 mm) 1331143 A8 B8 C8 D8 VI. Patent application base, N-{(R)-a-[2-(S)-2-(carboxy)-4- (R)-4-(hydroxy)pyrrolidin-1-ylcarbonyl]benzyl}aminoindenyloxy, N-{(R)-a-[2-(S)-2-(restrictive) ) p丫丁-1-ylcarbonyl]henyl}amino aryl 曱.oxy, N-{(R)-a-[N-{(S)-l-[N-((S) - 1-sulfoethyl)aminomethylmercapto]ethyl}aminocarbamimidyl]benzyl}aminopurinylmethoxy, &gt;^-{(foot)-〇:-[1^ -((尺)-1-carboxy-3,3-dimercaptobutyl)aminocarbonyl]hydrazino}aminocarbonylcarbonyl, N-{(R)-a-[N- Carboxy-3,3-dimercaptobutyl)aminoindenyl]hydrazino}aminoindolyloxy,^[-{(1〇-^*-[1^((11)-1) -carboxy-3,3-dimercaptobutyl)aminoindenyl]-4-hydroxybenzyl}aminomercaptomethoxy, N-((R)-a-{N-[(S -l-carboxy-2-(trimethyldecyl)ethyl]aminoindenyl}-4-hydroxybenzyl)aminocarboxamidooxy or N-((R) - a - {N-[(R)-1-carboxy-2-(trimethylsulfonyl)ethyl]aminocarbonyl}-4 -hydroxyindenyl)aminopurine Alkyloxy. 7. A compound of the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of: 1,1-dioxo-3,3-dibutyl-5-phenyl-7 -曱thio-8-(^[-{(R) - a - [N-((R)-1-carboxy-2-indolylethyl)aminoindolyl]-4-hydroxyindenyl) }aminomercaptopurineoxy)-2,3,4,5-tetrahydro-1,2,5-benzo-sephedoxin; 1,1-dioxo-3,3-di Butyl-5-phenyl-7-sulfonylthio-8-(1^-{(R) - a - [N-((S)-1-carboxy-2-(R)-hydroxypropyl)amine 4-mercapto]-4-hydroxybenzyl}aminomethylindolyloxy)-2,3,4,5-tetrahydro-1,2,5-benzoxanthene; 80189-990618 .doc -7- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1331143 A8 B8 C8 D8 VI. Patent application scope 1,1-dioxo-3,3-dibutyl-5- Phenyl-7-fluorenyl-8-(:^-{(R)-a-[N-((S)-l-carboxy-2-mercaptopropyl)aminoindenyl]-4 - Hydroxymercapto}aminoguanidinomethoxy)-2,3,4,5-tetrahydro-1,2,5-benzoxanthene; 1,1-dioxo-3,3 -Dibutyl-5-phenyl-7-methylthio-8-(1^-{(R)-a-[N-((S)-l-carboxybutyl)amino group Mercapto]-4-hydroxybenzyl}aminopurinyloxy)-2,3,4,5-tetrahydro-1,2,5-benzopyrimidine; 1.1-diox 3,3-dibutyl-5-phenyl-7-methylthio-8-(1^-{(R)-a-[N-((S)-l-carboxypropyl)amino group曱醯基]芊基}aminomercaptoalkyloxy)-2,3,4,5-tetrahydro-1,2,5-benzothiazepine, l,l-dioxo- 3,3-Dibutyl-5-phenyl-7-fluorenyl-8-(N-{(R)-a-[N-((S)-l-carboxyethyl)amino) fluorenyl芊 }}amino-mercaptomethoxy)-2,3,4,5-tetrahydro-1,2,5-benzothiazepine; 1.1-dioxo-3,3-di Butyl-5-phenyl-7-fluorenyl-8-(1^-{(R)-a-[N-((S)-l-carboxy-2-(R)-hydroxypropyl)amine , 芊 芊 } } } } } } } } } } } } } 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 1.1 ,3-dibutyl-5-phenyl-7-fluorenyl-8-(^[-{(R)-α-[N-(2-sulfoethyl)aminoindenyl]-4 -hydroxybenzyl}aminoguanidinomethoxy)-2,3,4,5-tetrahydro-1,2,5-benzo-4 dioxin; 80189-990618.doc -8- paper The scale applies to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1331143 A8 B8 C8 D8 VI. Patent application scope: 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(^4-{(R)-a-[N- ((S)-l-carboxyethyl)aminomethylindenyl]-4-hydroxybenzyl}aminoindenyloxy)-2,3,4,5-tetrahydro-1,2,5 -benzothiazepine; 1.1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(N-{(R)-a-[N-( (R)-l-carboxy-2-indolethioethyl)aminocarbamimidyl] benzyl}aminomethylindenyloxy)-2,3,4,5-tetrahydro-1,2, 5-benzopyrimidine; 1,1-dioxo-3,3-dibutyl-5-phenyl-7-methylthio-8-(1&lt;[-{(R) - a - [N-{(S)-1-[N-((S)-2-hydroxy-1-carboxyethyl)aminomethylmercapto]propyl}aminomethylindenyl]benzyl}aminopurine Mercaptomethoxy)-2,3,4,5-tetrahydro-1,2,5-benzopyridinium; and l,l-dioxo-3,3-dibutyl-5 -phenyl-7-methylthio-8-(N-{(R)-a-[N-((S)-l-carboxy-2-methylpropyl)aminoindenyl]benzyl} Aminomercaptomethoxy)-2,3,4,5-tetrahydro-1,2,5-benzopyrimidine. 8. A compound of the formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of the following: 1.1-dioxo-3,3-dibutyl-5-phenyl-7-indole Thioyl-8-(]^-{(R)-a-[N-((S)-l-carboxypropyl)aminocarbonyl]-4-hydroxycarbonyl}aminocarbonyl -2,3,4,5-tetrahydro-1,2,5-benzopyrene dioxime; and 1.1-dioxo-3,3-dibutyl-5-phenyl-7 -Methylthio-8-[1^-((R)-α-carboxy-4-hydroxybenzyl)aminomethylindenyloxy]- 80189-990618.doc -9- This paper scale applies to China Standard (CNS) A4 specification (210x297 mm) 1331143 AB c D VI. Patent application scope 2,3,4,5-tetrahydro-1,2,5-benzothiazepine. 9. A process for the preparation of a compound of formula (I), or a pharmaceutically acceptable salt thereof, according to claim 1 or 2, which process comprises: Process 1): a compound of formula (I) wherein X is -0- To make a compound of formula (Ila) or (lib): (Ha) reacting with a compound of formula (111) L wherein L is a replaceable group; Process 2): an acid of formula (IVa) or (IVb) 80189-990618.doc 10- This paper scale applies to China National Standard (CNS) A4 specification (210x297 mm) 1331143 A8 B8 C8 D8 VI. Patent application scope (IVb) (IVa) or an activated derivative thereof; reacting with an amine of formula (V): R NH (V) Process 3): For a compound of the formula (I) wherein R11 is a group of the formula (IB), a compound of the formula (I) wherein R11 is a carboxyl group is reacted with an amine of the formula (VI): For the compound, the compound of the formula (V11 a ) or (V11 b ) is used: -11 - 80l89-990618.doc This paper scale is applicable to the Chinese National Standard (CNS) A4 specification (210x297 mm) 1331143 A8 B8 C8 D8 VI. Patent application scope R1 R2 t X (Vila) (Vllb) wherein L is a replaceable group; reacts with a thiol of formula (yin): Rm-H (VIII) wherein 1^ is a C1-6 alkylthio group; and subsequently if desired or desired : i) removing any protecting groups; ii) forming a pharmaceutically acceptable salt. H). A compound of the formula (1) or a pharmaceutically acceptable salt thereof according to any one of claims i, 2 and 6 to 8, which is for use in medicine. 11. A compound of the formula (I) according to any one of claims 1, 2 and 6 to 8 or a pharmaceutically acceptable substance thereof. A further relates to a method for treating a warm-blooded animal such as a human. 12. A kind of cockroach used for warm-blooded animals such as humans, such as "the cockroach produces a tannin-bilbic acid transmission inhibitory effect and the five substances" include any of items i, 2 and 6 to 8 of the patent application scope. The compound of formula (1) or the more acceptable pharmaceutically acceptable diluent or carrier. 1 &gt;, medical music 13. The pharmaceutical composition J of claim 12 is used for the treatment of temperature 80189-990618.doc This paper is the time of the country @绪准 (CNS) A4 specifications (2〗 Qx297 public) 1331143 Α8 Β8 C8 D8 Sixth, the scope of patent application for blood animals such as human hyperlipidemia. 14. If you apply for the patent scope of the 12th medicine a composition useful for treating conditions and disorders of fatty disorders such as hyperlipidemia, triglyceride, high beta lipoproteinemia (high LDL), very high lipoproteinemia in warm-blooded animals such as humans (high VLDL), hyperlactinemia, hypolipoproteinemia, hypercholesterolemia, hyperlipoproteinemia, and high alpha lipoproteinemia (low HDL). 15. Pharmaceuticals as claimed in Article 12 a composition useful for treating different clinical conditions of a warm-blooded animal such as a human Congestion of atheroma, arteriosclerosis, irregular rhythm, high thrombosis, vascular dysfunction, endothelial dysfunction, cardiac disorders, coronary heart disease, cardiovascular disease, myocardial infarction, angina pectoris, peripheral vascular disease, cardiovascular tissue such as heart inflammation, valve , vascular distribution, arteries and veins, aneurysms, stenosis, restenosis, vascular plaques, vascular fat marks, white blood cells, single cell and/or invasive cell infiltration, intimal thickening, thinning of the middle layer of the arteries, infection and surgical trauma And vascular embolism, stroke and transient hematopoietic shock. 16. The pharmaceutical composition of claim 15 can be used for treating warm-blooded animals such as human atherosclerosis, coronary heart disease, myocardial infarction, angina pectoris, and distal end. Vascular disease, transient hemorrhagic shock. 13- 80189-990618.doc This paper size applies to China National Standard (CNS) A4 specification (210x297 mm)